Pub Date : 2026-01-23DOI: 10.1016/j.molimm.2026.01.004
Jingjing Cao , Huaxing Zhang , Yanhui Ni , Xiaoran Ning
{"title":"Corrigendum to “Neferine reduces synovial inflammation and cardiac complications in a collagen-induced arthritis mouse model via inhibiting NF-κB/NLRP3 inflammasome axis” [Mol. Immunol. 182 (2025) 117–125]","authors":"Jingjing Cao , Huaxing Zhang , Yanhui Ni , Xiaoran Ning","doi":"10.1016/j.molimm.2026.01.004","DOIUrl":"10.1016/j.molimm.2026.01.004","url":null,"abstract":"","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Page 110"},"PeriodicalIF":3.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1016/j.molimm.2026.01.003
Hong-My Nguyen , Britteny Cassaidy , Mark Collinge , James C. Hickey , Jin Li , Amir Arellano-Saab , Steven W. Kumpf , Mitchell Thorn
mRNA-LNPs offer a promising platform for therapeutic protein expression, however, achieving efficient and sustained translation remains a significant challenge. One of the major barriers to mRNA-LNP efficacy is the activation of innate immune responses that recognize foreign RNA and suppress subsequent protein synthesis. Among these, the OAS-RNase L pathway, involved in degradation of cytoplasmic mRNA, plays a key role. This study examined the impact of RNase L and RNase L blockade on mRNA-LNP expression efficiency. In THP-1 cells, which express high endogenous levels of RNase L, both genetic ablation and pharmacological inhibition of RNase L led to a marked increase in protein expression. In contrast, HeLa cells, which exhibit low RNase L expression, showed minimal response to RNase L inhibition. In human peripheral blood mononuclear cells (PBMCs), RNase L inhibition also enhanced mRNA expression, while blocking other RNA sensors such as TLR7/8, RIG-I, TLR3, or MAVS, did not. Activation of the OAS–RNase L pathway may be driven by double-stranded secondary structure formed by therapeutic mRNA, resulting in mRNA recognition and degradation. RNase L acts as a key post-transcriptional regulator of mRNA stability and translation. Targeting this pathway offers a strategy to improve the performance of mRNA-based therapeutics.
{"title":"Inhibition of RNase L enhances the expression efficiency of mRNA-LNPs","authors":"Hong-My Nguyen , Britteny Cassaidy , Mark Collinge , James C. Hickey , Jin Li , Amir Arellano-Saab , Steven W. Kumpf , Mitchell Thorn","doi":"10.1016/j.molimm.2026.01.003","DOIUrl":"10.1016/j.molimm.2026.01.003","url":null,"abstract":"<div><div>mRNA-LNPs offer a promising platform for therapeutic protein expression, however, achieving efficient and sustained translation remains a significant challenge. One of the major barriers to mRNA-LNP efficacy is the activation of innate immune responses that recognize foreign RNA and suppress subsequent protein synthesis. Among these, the OAS-RNase L pathway, involved in degradation of cytoplasmic mRNA, plays a key role. This study examined the impact of RNase L and RNase L blockade on mRNA-LNP expression efficiency. In THP-1 cells, which express high endogenous levels of RNase L, both genetic ablation and pharmacological inhibition of RNase L led to a marked increase in protein expression. In contrast, HeLa cells, which exhibit low RNase L expression, showed minimal response to RNase L inhibition. In human peripheral blood mononuclear cells (PBMCs), RNase L inhibition also enhanced mRNA expression, while blocking other RNA sensors such as TLR7/8, RIG-I, TLR3, or MAVS, did not. Activation of the OAS–RNase L pathway may be driven by double-stranded secondary structure formed by therapeutic mRNA, resulting in mRNA recognition and degradation. RNase L acts as a key post-transcriptional regulator of mRNA stability and translation. Targeting this pathway offers a strategy to improve the performance of mRNA-based therapeutics.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 101-109"},"PeriodicalIF":3.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.molimm.2026.01.005
Weiping Yan , Lei Wang , Wenting Zhu , Xiao Liu , Zihan Xu , Juntong Liu , Jie Ding , Mengling Zhu , Fenfen Ma , Zibo Dong
It has been shown that a high-salt diet (HSD) significantly damages the colonic epithelial barrier, resulting in increased intestinal permeability, upset gut microbial balance, and generalized inflammation. Despite this, effective therapeutic strategies to prevent HSD-induced intestinal damage remain limited. This study aims to explore the preventive properties and basic mechanisms of liquiritigenin (LG)，a natural flavonoid, against chronic colonic injury induced by prolonged HSD exposure. A murine model of chronic colitis was established by administering an 8 % NaCl diet, and LG therapy was used to evaluate how it affected the function of the intestinal barrier and allergic reactions. The development of pro- and anti-inflammatory cytokines (il-β, il-6, tnf-α, il-10, and inos) as well as important tight junction proteins (ZO-1, Claudin-3, and Occludin) was assessed. Furthermore, we investigated the molecular processes in vitro using normal colonic epithelial cell line NCM-460, with particular focus on the NF-κB and JAK/STAT3 signaling pathways. LG increased the expression of junction-binding proteins, greatly enhanced the intestinal wall integrity, and mitigated histopathological damage. Furthermore, it markedly attenuated excessive inflammatory responses both in vivo and in vitro. Mechanistically, LG suppressed the phosphorylation of key components within the pathways of JAK/STAT3 and NF-κB, thereby inhibiting downstream inflammatory signaling and epithelial cell injury. Collectively, these results demonstrate that liquiritigenin exerts protective effects against HSD-induced colonic damage by concurrently modulating the NF-κB and JAK/STAT3 pathways, highlighting its therapeutic potential for high salt-related intestinal disorders.
{"title":"Liquiritigenin regulates JAK/STAT3 and NF-κB signaling pathways to reduce colonic damage and barrier dysfunction caused by a high-salt diet","authors":"Weiping Yan , Lei Wang , Wenting Zhu , Xiao Liu , Zihan Xu , Juntong Liu , Jie Ding , Mengling Zhu , Fenfen Ma , Zibo Dong","doi":"10.1016/j.molimm.2026.01.005","DOIUrl":"10.1016/j.molimm.2026.01.005","url":null,"abstract":"<div><div>It has been shown that a high-salt diet (HSD) significantly damages the colonic epithelial barrier, resulting in increased intestinal permeability, upset gut microbial balance, and generalized inflammation. Despite this, effective therapeutic strategies to prevent HSD-induced intestinal damage remain limited. This study aims to explore the preventive properties and basic mechanisms of liquiritigenin (LG)，a natural flavonoid, against chronic colonic injury induced by prolonged HSD exposure. A murine model of chronic colitis was established by administering an 8 % NaCl diet, and LG therapy was used to evaluate how it affected the function of the intestinal barrier and allergic reactions. The development of pro- and anti-inflammatory cytokines (<em>il-β</em>, <em>il-6</em>, <em>tnf-α, il-10</em>, and <em>inos</em>) as well as important tight junction proteins (ZO-1, Claudin-3, and Occludin) was assessed. Furthermore, we investigated the molecular processes <em>in vitro</em> using normal colonic epithelial cell line NCM-460, with particular focus on the NF-κB and JAK/STAT3 signaling pathways. LG increased the expression of junction-binding proteins, greatly enhanced the intestinal wall integrity, and mitigated histopathological damage. Furthermore, it markedly attenuated excessive inflammatory responses both <em>in vivo</em> and <em>in vitro</em>. Mechanistically, LG suppressed the phosphorylation of key components within the pathways of JAK/STAT3 and NF-κB, thereby inhibiting downstream inflammatory signaling and epithelial cell injury. Collectively, these results demonstrate that liquiritigenin exerts protective effects against HSD-induced colonic damage by concurrently modulating the NF-κB and JAK/STAT3 pathways, highlighting its therapeutic potential for high salt-related intestinal disorders.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 86-100"},"PeriodicalIF":3.0,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1016/j.molimm.2026.01.002
Zhijie Chen , Zhiwu Xia , Liping Chen , Qingqing Nie , Wang Gong , Wenqiang Cao , Xue Wang , Yuehong Zou , Shuai Zhang , Yuchen Yang , Menghong Yang , Jiaming Yang , Yanna Liu , Lehong Zhang , Wenjie Fang , Yixin Chen , Junlong Zhao , Ziyan Meng
To mitigate the APC cytotoxicity associated with simvastatin (a promising adjuvant candidate), we encapsulated this drug in liposomes to generate LIPO-SIM, and explored the potential and mechanism. Formulated via ethanol injection and rotary evaporation, liposome-SIM was characterized for appearance, ζ-average, PDI, zeta potential, and encapsulation efficiency. C57BL/6 J mice were immunized with LIPO-SIM + OVA (0/21-day schedule), euthanized on day 28 to evaluate immunogenicity, safety, and antigen presentation mechanisms. In vitro, DC2.4 cells stimulated with liposome-SIM underwent RNA-Seq, metabolomics, and western blotting to clarify adjuvant mechanisms. Results showed liposome-SIM significantly increased anti-OVA IgG titers and cellular immunity, activated local lymph node macrophages/dendritic cells, and enhanced MHC-I presentation. In vitro, AMPK inhibition and NF-κB activation were observed. No organ toxicity or inflammatory storms were detected. Liposome-SIM enhances cellular immunity via the MHC-I pathway, with AMPK/NF-κB signaling as a potential key mechanism.
{"title":"Liposome-mediated simvastatin in vaccine adjuvants: Its application and mechanism","authors":"Zhijie Chen , Zhiwu Xia , Liping Chen , Qingqing Nie , Wang Gong , Wenqiang Cao , Xue Wang , Yuehong Zou , Shuai Zhang , Yuchen Yang , Menghong Yang , Jiaming Yang , Yanna Liu , Lehong Zhang , Wenjie Fang , Yixin Chen , Junlong Zhao , Ziyan Meng","doi":"10.1016/j.molimm.2026.01.002","DOIUrl":"10.1016/j.molimm.2026.01.002","url":null,"abstract":"<div><div>To mitigate the APC cytotoxicity associated with simvastatin (a promising adjuvant candidate), we encapsulated this drug in liposomes to generate LIPO-SIM, and explored the potential and mechanism. Formulated via ethanol injection and rotary evaporation, liposome-SIM was characterized for appearance, ζ-average, PDI, zeta potential, and encapsulation efficiency. C57BL/6 J mice were immunized with LIPO-SIM + OVA (0/21-day schedule), euthanized on day 28 to evaluate immunogenicity, safety, and antigen presentation mechanisms. In vitro, DC2.4 cells stimulated with liposome-SIM underwent RNA-Seq, metabolomics, and western blotting to clarify adjuvant mechanisms. Results showed liposome-SIM significantly increased anti-OVA IgG titers and cellular immunity, activated local lymph node macrophages/dendritic cells, and enhanced MHC-I presentation. In vitro, AMPK inhibition and NF-κB activation were observed. No organ toxicity or inflammatory storms were detected. Liposome-SIM enhances cellular immunity via the MHC-I pathway, with AMPK/NF-κB signaling as a potential key mechanism.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 72-85"},"PeriodicalIF":3.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.molimm.2026.01.001
Shaomei Wu , Wei Zhou , Hong Duo , Jian You, Yuanyuan Chen, Siqi Du, Ningbo Ku, Jun Luo, Zhongzhong Liu, Qifa Ye
<div><div>Hepatic ischemia-reperfusion injury (HIRI) is a common and inevitable pathological event during liver transplantation and hepatectomy, which significantly impairs postoperative liver function recovery and patient prognosis. However, the molecular and cellular mechanisms of HIRI have not been fully elucidated and further research is urgently needed. In recent years, the rapid development of bioinformatics analysis technology and the research method combining multi-dimensional data mining with experimental verification have become important strategies for exploring the mechanisms of complex diseases. Building on this, this study aims to screen and analyze the potential roles and mechanisms of key regulatory factors in the process of HIRI through systematic bioinformatics analysis and experimental verification, providing a basis for clarifying its pathogenesis and finding potential therapeutic targets. In this study, two transcriptome microarray datasets (GSE14951 and GSE7706) of human liver tissue were systematically analyzed, and candidate genes related to IRI were initially screened through differential expression analysis. Combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, protein–protein interaction (PPI) network construction and modular analysis were performed to identify potential key regulatory factors, ultimately highlighting HSPH1 and DNAJB1. Subsequently, based on a mouse liver IRI model, paired reperfusion tissue samples from clinical liver transplant patients, and an AML12 cell hypoxia/reoxygenation (H/R) model, the two genes were experimentally validated from multiple perspectives, including transcriptional expression, protein levels, and subcellular localization. A combination of quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC), immunofluorescence (IF), and co-immunoprecipitation (Co-IP) was employed to comprehensively evaluate their expression dynamics, subcellular distribution, and protein–protein interaction characteristics. Differential expression analysis identified 154 genes with consistent expression trends across the two datasets, which were significantly enriched in metabolic, stress response, inflammatory, and protein folding pathways. PPI network construction and module analysis further identified HSPH1 and DNAJB1 as core components of a heat shock protein interaction cluster. Validation using a mouse IRI model, paired reperfusion tissue samples from clinical liver transplant patients, and an AML12 cell hypoxia/reoxygenation (H/R) model demonstrated that both genes were significantly upregulated under IRI conditions, localized in the cytosol, and exhibited co-localization and physical interaction. Transcription factor prediction analysis suggested that STAT3 and NR1I2 might be involved in their transcriptional regulation.</div><div>In conclusion, HSPH1 and DNAJB1 are co-expressed and physically interact in hepatic IRI, suggesting th
{"title":"HSPH1 and DNAJB1 as potential key regulators in hepatic ischemia-reperfusion injury","authors":"Shaomei Wu , Wei Zhou , Hong Duo , Jian You, Yuanyuan Chen, Siqi Du, Ningbo Ku, Jun Luo, Zhongzhong Liu, Qifa Ye","doi":"10.1016/j.molimm.2026.01.001","DOIUrl":"10.1016/j.molimm.2026.01.001","url":null,"abstract":"<div><div>Hepatic ischemia-reperfusion injury (HIRI) is a common and inevitable pathological event during liver transplantation and hepatectomy, which significantly impairs postoperative liver function recovery and patient prognosis. However, the molecular and cellular mechanisms of HIRI have not been fully elucidated and further research is urgently needed. In recent years, the rapid development of bioinformatics analysis technology and the research method combining multi-dimensional data mining with experimental verification have become important strategies for exploring the mechanisms of complex diseases. Building on this, this study aims to screen and analyze the potential roles and mechanisms of key regulatory factors in the process of HIRI through systematic bioinformatics analysis and experimental verification, providing a basis for clarifying its pathogenesis and finding potential therapeutic targets. In this study, two transcriptome microarray datasets (GSE14951 and GSE7706) of human liver tissue were systematically analyzed, and candidate genes related to IRI were initially screened through differential expression analysis. Combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, protein–protein interaction (PPI) network construction and modular analysis were performed to identify potential key regulatory factors, ultimately highlighting HSPH1 and DNAJB1. Subsequently, based on a mouse liver IRI model, paired reperfusion tissue samples from clinical liver transplant patients, and an AML12 cell hypoxia/reoxygenation (H/R) model, the two genes were experimentally validated from multiple perspectives, including transcriptional expression, protein levels, and subcellular localization. A combination of quantitative PCR (qPCR), Western blotting, immunohistochemistry (IHC), immunofluorescence (IF), and co-immunoprecipitation (Co-IP) was employed to comprehensively evaluate their expression dynamics, subcellular distribution, and protein–protein interaction characteristics. Differential expression analysis identified 154 genes with consistent expression trends across the two datasets, which were significantly enriched in metabolic, stress response, inflammatory, and protein folding pathways. PPI network construction and module analysis further identified HSPH1 and DNAJB1 as core components of a heat shock protein interaction cluster. Validation using a mouse IRI model, paired reperfusion tissue samples from clinical liver transplant patients, and an AML12 cell hypoxia/reoxygenation (H/R) model demonstrated that both genes were significantly upregulated under IRI conditions, localized in the cytosol, and exhibited co-localization and physical interaction. Transcription factor prediction analysis suggested that STAT3 and NR1I2 might be involved in their transcriptional regulation.</div><div>In conclusion, HSPH1 and DNAJB1 are co-expressed and physically interact in hepatic IRI, suggesting th","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 56-71"},"PeriodicalIF":3.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.molimm.2025.12.015
Chunlei He , Junhua Zhang , Geer Deli , Kai Zhao , Lulin Liu , Baojian Lai , Meiyu Hu , Huabin He
Background
Arthritis is an inflammatory disease characterized by multifactorial pathogenesis in joints or surrounding tissues. M1 macrophage polarization is a key pathological feature of arthritis, and m⁵C RNA modification has been implicated in disease progression. This study aimed to elucidate the role of NSUN2, a writer of m⁵C modification, in modulating arthritis development.
Methods
LPS-stimulated RAW264.7 cell models and collagen-induced arthritis (CIA) rat models were established. M1 and M2 macrophage polarization was assessed by detecting cell surface markers and pro-inflammatory cytokines using immunofluorescence, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time PCR. Underlying mechanisms were investigated via methylated RNA immunoprecipitation (MeRIP), Co-immunoprecipitation (Co-IP), and Dual-Luciferase reporter assays.
Results
Downregulation of NSUN2 significantly inhibited M1 polarization and promoted M2 activation both in vitro and in vivo. NSUN2 enhanced m5C modification of CCL2, stabilized its mRNA expression, and facilitated its interaction with CCR2. Furthermore, NSUN2 activated the NF-κB signaling pathway in macrophages. Notably, inhibition of CCL2 activity abrogated the effects of NSUN2 on macrophage polarization.
Conclusion
NSUN2 drives M1 macrophage polarization through m5C modification of CCL2, thereby exacerbating arthritis progression. Targeting NSUN2 may alleviate inflammatory responses, offering a novel therapeutic strategy for arthritis treatment.
{"title":"NSUN2 aggravates M1 macrophage polarization in arthritis progression through m5C modification of CCL2","authors":"Chunlei He , Junhua Zhang , Geer Deli , Kai Zhao , Lulin Liu , Baojian Lai , Meiyu Hu , Huabin He","doi":"10.1016/j.molimm.2025.12.015","DOIUrl":"10.1016/j.molimm.2025.12.015","url":null,"abstract":"<div><h3>Background</h3><div>Arthritis is an inflammatory disease characterized by multifactorial pathogenesis in joints or surrounding tissues. M1 macrophage polarization is a key pathological feature of arthritis, and m⁵C RNA modification has been implicated in disease progression. This study aimed to elucidate the role of NSUN2, a writer of m⁵C modification, in modulating arthritis development.</div></div><div><h3>Methods</h3><div>LPS-stimulated RAW264.7 cell models and collagen-induced arthritis (CIA) rat models were established. M1 and M2 macrophage polarization was assessed by detecting cell surface markers and pro-inflammatory cytokines using immunofluorescence, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time PCR. Underlying mechanisms were investigated via methylated RNA immunoprecipitation (MeRIP), Co-immunoprecipitation (Co-IP), and Dual-Luciferase reporter assays.</div></div><div><h3>Results</h3><div>Downregulation of NSUN2 significantly inhibited M1 polarization and promoted M2 activation both <em>in vitro</em> and <em>in vivo</em>. NSUN2 enhanced m5C modification of CCL2, stabilized its mRNA expression, and facilitated its interaction with CCR2. Furthermore, NSUN2 activated the NF-κB signaling pathway in macrophages. Notably, inhibition of CCL2 activity abrogated the effects of NSUN2 on macrophage polarization.</div></div><div><h3>Conclusion</h3><div>NSUN2 drives M1 macrophage polarization through m5C modification of CCL2, thereby exacerbating arthritis progression. Targeting NSUN2 may alleviate inflammatory responses, offering a novel therapeutic strategy for arthritis treatment.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 45-55"},"PeriodicalIF":3.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145928051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.molimm.2025.12.014
Yu Luo , Yan Chen , Suning Huang , Haimin Zhu , Tianqi Zhao , Shiyu Feng , Fei Ma , Yan Ning , Jiaman Wu
Acupuncture is a popular therapeutic therapy for premature ovarian insufficiency (POI). The specific effect and the underlying mechanism of Guanyuan acupoint on the ovarian function of POI model mice remain unclear. The female C57BL6 mice were injected peritoneally with 12 mg/kg busulfan and 120 mg/kg cyclophosphamide to induce POI. The acupuncture intervention at Guanyuan acupoint was performed on the second day after the modeling. Vaginal smears were used to monitor the estrous cycle. The hematoxylin and eosin (H&E) staining was used to observe the morphological changes of ovarian tissue, and the TUNEL fluorescence staining assay was carried out to detect the apoptotic level of granulosa cells. The sex hormone levels were monitored as well. RNA sequencing was performed to select candidate gene which was regulated by acupuncture. Finally, the upstream lactating modification mechanism of Rictor was further investigated. The results showed that acupuncture at Guanyuan acupoint increased the number of vaginal exfoliated cells and inhibited the apoptosis of granulosa cell in POI model mice. Sex hormone levels indicated a marked decrease in AMH and E2 in POI group, with a concurrent significant rise in FSH levels. Furthermore, the Rictor/mTOR pathway was inactivated in POI model group, while was prominently activated by acupuncture at Guanyuan acupoint. Acupuncture intervened H3K18la to increase Rictor promoter activity in POI. In conclusion, acupuncture at Guanyuan acupoint increased body and ovarian weight, improved ovarian tissue morphology and structure, improved follicle development, and regulated ovarian function in POI model mice. This might be related to the activation of the Rictor/mTOR pathway.
{"title":"Acupuncture alleviates premature ovarian insufficiency via Rictor/mTOR pathway in mice by stimulating the Guanyuan acupoint","authors":"Yu Luo , Yan Chen , Suning Huang , Haimin Zhu , Tianqi Zhao , Shiyu Feng , Fei Ma , Yan Ning , Jiaman Wu","doi":"10.1016/j.molimm.2025.12.014","DOIUrl":"10.1016/j.molimm.2025.12.014","url":null,"abstract":"<div><div>Acupuncture is a popular therapeutic therapy for premature ovarian insufficiency (POI). The specific effect and the underlying mechanism of Guanyuan acupoint on the ovarian function of POI model mice remain unclear. The female C57BL6 mice were injected peritoneally with 12 mg/kg busulfan and 120 mg/kg cyclophosphamide to induce POI. The acupuncture intervention at Guanyuan acupoint was performed on the second day after the modeling. Vaginal smears were used to monitor the estrous cycle. The hematoxylin and eosin (H&E) staining was used to observe the morphological changes of ovarian tissue, and the TUNEL fluorescence staining assay was carried out to detect the apoptotic level of granulosa cells. The sex hormone levels were monitored as well. RNA sequencing was performed to select candidate gene which was regulated by acupuncture. Finally, the upstream lactating modification mechanism of Rictor was further investigated. The results showed that acupuncture at Guanyuan acupoint increased the number of vaginal exfoliated cells and inhibited the apoptosis of granulosa cell in POI model mice. Sex hormone levels indicated a marked decrease in AMH and E<sub>2</sub> in POI group, with a concurrent significant rise in FSH levels. Furthermore, the Rictor/mTOR pathway was inactivated in POI model group, while was prominently activated by acupuncture at Guanyuan acupoint. Acupuncture intervened H3K18la to increase Rictor promoter activity in POI. In conclusion, acupuncture at Guanyuan acupoint increased body and ovarian weight, improved ovarian tissue morphology and structure, improved follicle development, and regulated ovarian function in POI model mice. This might be related to the activation of the Rictor/mTOR pathway.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 34-44"},"PeriodicalIF":3.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145928050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1016/j.molimm.2025.12.013
Jie Fan , Farooq Riaz , Fan Pan
The Hippo signaling pathway is a fundamental regulator of organ growth, tissue regeneration, and cellular homeostasis, with far-reaching implications in cancer biology and immunology. Dysregulation of this pathway, particularly through its downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), is closely associated with oncogenic transformation and the establishment of an immunosuppressive tumor microenvironment (TME). This review discusses current knowledge on the multifaceted roles of Hippo signaling in cancer, focusing on its interactions with T cell–mediated immunity and mechanisms of tumor immune regulation. Aberrant YAP/TAZ activation enhances cancer cell proliferation, remodels the TME, and reprograms immune responses to favor tumor growth and immune evasion. The review explores how modulation of Hippo pathway components influences both tumor progression and immune cell function, highlighting its central role in shaping anti-tumor immunity. Furthermore, the therapeutic potential of targeting YAP/TAZ signaling is discussed in the context of advancing precision medicine and improving immunotherapeutic outcomes. Collectively, this work highlights the Hippo signaling cascade as both a key driver of tumorigenesis and a crucial regulator of immune modulation. A comprehensive understanding of its molecular interactions with T cells and the TME will support the development of innovative YAP/TAZ-targeted strategies that integrate molecular signaling and immune modulation, offering new directions for effective cancer therapy.
{"title":"Hippo signaling as a therapeutic switch for T cell functions and tumor immunity","authors":"Jie Fan , Farooq Riaz , Fan Pan","doi":"10.1016/j.molimm.2025.12.013","DOIUrl":"10.1016/j.molimm.2025.12.013","url":null,"abstract":"<div><div>The Hippo signaling pathway is a fundamental regulator of organ growth, tissue regeneration, and cellular homeostasis, with far-reaching implications in cancer biology and immunology. Dysregulation of this pathway, particularly through its downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), is closely associated with oncogenic transformation and the establishment of an immunosuppressive tumor microenvironment (TME). This review discusses current knowledge on the multifaceted roles of Hippo signaling in cancer, focusing on its interactions with T cell–mediated immunity and mechanisms of tumor immune regulation. Aberrant YAP/TAZ activation enhances cancer cell proliferation, remodels the TME, and reprograms immune responses to favor tumor growth and immune evasion. The review explores how modulation of Hippo pathway components influences both tumor progression and immune cell function, highlighting its central role in shaping anti-tumor immunity. Furthermore, the therapeutic potential of targeting YAP/TAZ signaling is discussed in the context of advancing precision medicine and improving immunotherapeutic outcomes. Collectively, this work highlights the Hippo signaling cascade as both a key driver of tumorigenesis and a crucial regulator of immune modulation. A comprehensive understanding of its molecular interactions with T cells and the TME will support the development of innovative YAP/TAZ-targeted strategies that integrate molecular signaling and immune modulation, offering new directions for effective cancer therapy.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 11-20"},"PeriodicalIF":3.0,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145886476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1016/j.molimm.2025.12.010
Huiyuan Li , Jiaer Ke , Yanli Zhou , Huanhuan Chen , Xufang Wu , Huoliang Liu , Juan Li
Background
Traditional Chinese medicine (TCM) has shown great promise in treating diabetic nephropathy (DN). However, the key targets and mechanisms underlying the therapeutic effects of the active ingredients of modified prescription Jiawei Qihuangyin (JWQHY) remain unclear.
Methods
Network pharmacology analysis was employed to identify potential targets of JWQHY in DN. Protein–protein interaction (PPI) and TCM component–target networks were constructed, and KEGG pathway enrichment analysis was performed to determine key therapeutic targets and signaling pathways. Molecular docking suggested an interaction between the major active compound formononetin (FMN) and the central target silent information regulator 1 (SIRT1), which was experimentally validated using cellular thermal shift assay. SIRT1 expression in podocytes was assessed by qRT-PCR and western blotting (WB). Cell viability (CCK-8), apoptosis (flow cytometry), and proinflammatory cytokine secretion (ELISA) were measured to evaluate podocyte injury. The acetylation level of NF-κB p65 and epithelial–mesenchymal transition (EMT)-related proteins were analyzed by WB. In vivo, a DN rat model was established to assess the therapeutic efficacy of JWQHY through biochemical urine analysis, histopathological examination (HE staining), and WB detection of SIRT1, acetylated NF-κB p65, and EMT markers.
Results
Network pharmacology identified 52 potential overlapping targets of JWQHY in DN, primarily associated with the NF-κB pathway. Among these, SIRT1 was predicted and experimentally confirmed as the main target of FMN. In a high-glucose–induced podocyte injury model, FMN upregulated SIRT1 expression, promoted NF-κB p65 deacetylation, and inhibited podocyte EMT. Consistently, FMN treatment improved renal function, reduced podocyte injury, and modulated SIRT1/NF-κB signaling in DN rats.
Conclusion
JWQHY exerts therapeutic effects in diabetic nephropathy by modulating the SIRT1/NF-κB signaling axis through its active compound formononetin, thereby inhibiting podocyte EMT. These findings provide mechanistic insight into the pharmacological basis of FMN and support its clinical potential in DN treatment.
{"title":"Formononetin in Jiawei Qihuangyin inhibits podocyte epithelial–mesenchymal transition and ameliorates diabetic nephropathy via SIRT1/NF-κB axis","authors":"Huiyuan Li , Jiaer Ke , Yanli Zhou , Huanhuan Chen , Xufang Wu , Huoliang Liu , Juan Li","doi":"10.1016/j.molimm.2025.12.010","DOIUrl":"10.1016/j.molimm.2025.12.010","url":null,"abstract":"<div><h3>Background</h3><div>Traditional Chinese medicine (TCM) has shown great promise in treating diabetic nephropathy (DN). However, the key targets and mechanisms underlying the therapeutic effects of the active ingredients of modified prescription Jiawei Qihuangyin (JWQHY) remain unclear.</div></div><div><h3>Methods</h3><div>Network pharmacology analysis was employed to identify potential targets of JWQHY in DN. Protein–protein interaction (PPI) and TCM component–target networks were constructed, and KEGG pathway enrichment analysis was performed to determine key therapeutic targets and signaling pathways. Molecular docking suggested an interaction between the major active compound formononetin (FMN) and the central target silent information regulator 1 (SIRT1), which was experimentally validated using cellular thermal shift assay. SIRT1 expression in podocytes was assessed by qRT-PCR and western blotting (WB). Cell viability (CCK-8), apoptosis (flow cytometry), and proinflammatory cytokine secretion (ELISA) were measured to evaluate podocyte injury. The acetylation level of NF-κB p65 and epithelial–mesenchymal transition (EMT)-related proteins were analyzed by WB. In vivo, a DN rat model was established to assess the therapeutic efficacy of JWQHY through biochemical urine analysis, histopathological examination (HE staining), and WB detection of SIRT1, acetylated NF-κB p65, and EMT markers.</div></div><div><h3>Results</h3><div>Network pharmacology identified 52 potential overlapping targets of JWQHY in DN, primarily associated with the NF-κB pathway. Among these, SIRT1 was predicted and experimentally confirmed as the main target of FMN. In a high-glucose–induced podocyte injury model, FMN upregulated SIRT1 expression, promoted NF-κB p65 deacetylation, and inhibited podocyte EMT. Consistently, FMN treatment improved renal function, reduced podocyte injury, and modulated SIRT1/NF-κB signaling in DN rats.</div></div><div><h3>Conclusion</h3><div>JWQHY exerts therapeutic effects in diabetic nephropathy by modulating the SIRT1/NF-κB signaling axis through its active compound formononetin, thereby inhibiting podocyte EMT. These findings provide mechanistic insight into the pharmacological basis of FMN and support its clinical potential in DN treatment.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 1-10"},"PeriodicalIF":3.0,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145886474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1016/j.molimm.2025.12.012
Lang Lin , Yuzhen Jia , Rubing Xue , Yutong Shi , Dahong Li , Fanxing Xu , Chun Chu
The chronic hyperglycemia and its-associated metabolic changes often lead to impaired wound healing, which seriously affects the quality of life of diabetic patients. Oxidative stress and apoptosis are key factors that impede epidermal cell proliferation and migration and delay wound healing. The aim of this study was to investigate the protective effect of a novel hydrogen sulfide (H2S)-releasing oridonin derivative (OAc-Ph-ADT) on epidermal HaCaT cells against a high-glucose and high-fat environment in vitro. Mechanistic studies showed that OAc-Ph-ADT exerted its antioxidant effects by activating the PI3K/AKT/Nrf2 signaling pathway. Specifically, it increased PI3K and phosphorylated-AKT expression, and promotes Nrf2 nuclear translocation, which in turn enhances the mRNA and protein expression of downstream antioxidant factors (HO-1, SOD2 and NQO1). In addition, OAc-Ph-ADT significantly reduced apoptosis by inhibiting the decrease in mitochondrial membrane potential and decreasing the expression of apoptosis-related proteins (Bax, Cleaved-Caspase 3/9). It was also observed that OAc-Ph-ADT up-regulated the expression of cystathionine β-synthase (CBS) via Nrf2, which further promoted the synthesis of endogenous H2S, resulting in positive feedback regulation. In summary, this paper elucidated through systematic in vitro experiments that OAc-Ph-ADT has a protective effect against epidermal cell damage in a high-glucose and high-fat environment, revealing its potential as a candidate molecule for diabetic wound treatment, and this novel H2S-releasing oridonin derivative has a potential application as a diabetic wound healing promoter.
{"title":"An H₂S-releasing oridonin derivative protects HaCaT cells against metabolic stress via PI3K/AKT/Nrf2 signaling","authors":"Lang Lin , Yuzhen Jia , Rubing Xue , Yutong Shi , Dahong Li , Fanxing Xu , Chun Chu","doi":"10.1016/j.molimm.2025.12.012","DOIUrl":"10.1016/j.molimm.2025.12.012","url":null,"abstract":"<div><div>The chronic hyperglycemia and its-associated metabolic changes often lead to impaired wound healing, which seriously affects the quality of life of diabetic patients. Oxidative stress and apoptosis are key factors that impede epidermal cell proliferation and migration and delay wound healing. The aim of this study was to investigate the protective effect of a novel hydrogen sulfide (H<sub>2</sub>S)-releasing oridonin derivative (OAc-Ph-ADT) on epidermal HaCaT cells against a high-glucose and high-fat environment <em>in vitro</em>. Mechanistic studies showed that OAc-Ph-ADT exerted its antioxidant effects by activating the PI3K/AKT/Nrf2 signaling pathway. Specifically, it increased PI3K and phosphorylated-AKT expression, and promotes Nrf2 nuclear translocation, which in turn enhances the mRNA and protein expression of downstream antioxidant factors (HO-1, SOD2 and NQO1). In addition, OAc-Ph-ADT significantly reduced apoptosis by inhibiting the decrease in mitochondrial membrane potential and decreasing the expression of apoptosis-related proteins (Bax, Cleaved-Caspase 3/9). It was also observed that OAc-Ph-ADT up-regulated the expression of cystathionine β-synthase (CBS) via Nrf2, which further promoted the synthesis of endogenous H<sub>2</sub>S, resulting in positive feedback regulation. In summary, this paper elucidated through systematic <em>in vitro</em> experiments that OAc-Ph-ADT has a protective effect against epidermal cell damage in a high-glucose and high-fat environment, revealing its potential as a candidate molecule for diabetic wound treatment, and this novel H<sub>2</sub>S-releasing oridonin derivative has a potential application as a diabetic wound healing promoter.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 21-33"},"PeriodicalIF":3.0,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145886475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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