Pub Date : 2026-03-01Epub Date: 2025-12-17DOI: 10.1016/j.bbadis.2025.168144
Benjamin R. Pryce , Haiming L. Kerr
Cancer cachexia is characterized by a significant loss in body weight due to the wasting of skeletal muscle and adipose tissue. Systemic inflammation has long been associated with cachexia, with various tumor secreted factors shown to correlate with as well as cause tissue wasting. In addition to systemic inflammation, it has become increasingly appreciated that inflammation occurs in specific tissues in cancer cachexia, with tissues such as muscle, adipose, liver and brain being affected. While several studies have shown that this local tissue inflammation contributes to cachexia, there is evidence that some aspects of the inflammatory response may play a protective role to mitigate tissue wasting. Here, we will review the findings on local tissue inflammation in cachexia, comparing the impacts of such inflammation on tissue wasting and cachexia progression overall. Furthermore, we discuss the methods used to mitigate inflammation in various tissues and highlight the outcomes on the cachectic phenotype. Collectively, understanding how inflammation contributes to cachexia in each tissue will ultimately influence how therapies can be designed to treat cachexia while minimizing possible adverse side effects.
{"title":"The effects of tissue inflammation on cancer cachexia","authors":"Benjamin R. Pryce , Haiming L. Kerr","doi":"10.1016/j.bbadis.2025.168144","DOIUrl":"10.1016/j.bbadis.2025.168144","url":null,"abstract":"<div><div>Cancer cachexia is characterized by a significant loss in body weight due to the wasting of skeletal muscle and adipose tissue. Systemic inflammation has long been associated with cachexia, with various tumor secreted factors shown to correlate with as well as cause tissue wasting. In addition to systemic inflammation, it has become increasingly appreciated that inflammation occurs in specific tissues in cancer cachexia, with tissues such as muscle, adipose, liver and brain being affected. While several studies have shown that this local tissue inflammation contributes to cachexia, there is evidence that some aspects of the inflammatory response may play a protective role to mitigate tissue wasting. Here, we will review the findings on local tissue inflammation in cachexia, comparing the impacts of such inflammation on tissue wasting and cachexia progression overall. Furthermore, we discuss the methods used to mitigate inflammation in various tissues and highlight the outcomes on the cachectic phenotype. Collectively, understanding how inflammation contributes to cachexia in each tissue will ultimately influence how therapies can be designed to treat cachexia while minimizing possible adverse side effects.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168144"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-24DOI: 10.1016/j.bbadis.2025.168123
Wenzhi Liu , Lu Zhang , Yixin Wang , Xiaohong Jiang , Jinting Tan , Ying Zhang , Yuanyuan Fu
Astragalus polysaccharides (APS) show promising effects in preventing tumor progression and immune escape. This study investigated the mechanism of APS in immune escape in cervical cancer (CC). The effects of different APS concentrations on the viability of CC cell lines (HeLa and SiHa) were determined. Immune evasion by CC cells was examined after APS treatment. An in vivo model was constructed by subcutaneous injection of U14 cells, and the effect of APS on immune evasion was investigated. APS downstream targets were screened using multiple databases, and the regulatory relationship between APS and NR3C2 was verified. Bioinformatics analysis was conducted to identify the downstream molecules of NR3C2, and the regulatory mechanism was validated. The effects of NR3C2 and SLC40A1 on immune escape were tested in vivo and in vitro. APS inhibited immune escape in CC and activated NR3C2 expression and CD8+ T cell function. NR3C2 knockdown reversed the inhibitory effects of APS on immune escape and malignant behaviors of CC cells. NR3C2 was enriched in the SLC40A1 promoter and promoted SLC40A1 expression. SLC40A1 upregulation enhanced the inhibitory effect of APS on immune escape in CC. APS inhibits immune escape of CC by targeting NR3C2 and activating SLC40A1.
{"title":"Astragalus polysaccharide hinders cervical cancer immune escape by targeting NR3C2 and activating SLC40A1","authors":"Wenzhi Liu , Lu Zhang , Yixin Wang , Xiaohong Jiang , Jinting Tan , Ying Zhang , Yuanyuan Fu","doi":"10.1016/j.bbadis.2025.168123","DOIUrl":"10.1016/j.bbadis.2025.168123","url":null,"abstract":"<div><div>Astragalus polysaccharides (APS) show promising effects in preventing tumor progression and immune escape. This study investigated the mechanism of APS in immune escape in cervical cancer (CC). The effects of different APS concentrations on the viability of CC cell lines (HeLa and SiHa) were determined. Immune evasion by CC cells was examined after APS treatment. An <em>in vivo</em> model was constructed by subcutaneous injection of U14 cells, and the effect of APS on immune evasion was investigated. APS downstream targets were screened using multiple databases, and the regulatory relationship between APS and NR3C2 was verified. Bioinformatics analysis was conducted to identify the downstream molecules of NR3C2, and the regulatory mechanism was validated. The effects of NR3C2 and SLC40A1 on immune escape were tested <em>in vivo</em> and <em>in vitro</em>. APS inhibited immune escape in CC and activated NR3C2 expression and CD8<sup>+</sup> T cell function. NR3C2 knockdown reversed the inhibitory effects of APS on immune escape and malignant behaviors of CC cells. NR3C2 was enriched in the SLC40A1 promoter and promoted SLC40A1 expression. SLC40A1 upregulation enhanced the inhibitory effect of APS on immune escape in CC. APS inhibits immune escape of CC by targeting NR3C2 and activating SLC40A1.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168123"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-31DOI: 10.1016/j.bbadis.2025.168150
Chen Liu , Wentao Liu , Yuan Wang , Chengzhi Jiang , Sheng Chen , Qianqian Huang , Xiaowei Xiong , Li Wang , Guohua Zeng , Qiren Huang
Osteopontin (OPN), a glycosylated protein ubiquitously in cellular matrix, exhibits a low expression in normal myocardial tissue but a high expression in fibrotic myocardial tissue. However, the action and mechanisms of OPN on the pathogenesis of myocardial fibrosis (MF) remain unclear. The purpose of the study is to investigate the action and mechanisms of OPN on the occurrence and development of MF, emphasizing abnormal activation of cardiac fibroblasts (CFs) and extracellular matrix (ECM) deposition. Both NIH-3T3 cells and C57BL/6 J mice were infected with OPN over-expression adenoviruses (Ad-Spp1). Cardiac function and fibrosis degree were evaluated in the presence and absence of angiotensin (AngII) (in vitro) or isoprenaline (ISO) (in vivo). Our data demonstrate that OPN over-expression results in myocardial injury and ECM accumulation under the physiological condition. Moreover, it exacerbates such effects under the pathological condition induced by AngII or ISO; in contrast, OPN knockdown attenuates the fibrotic response in vitro induced by AngII. Interestingly, OPN significantly promotes phenotypic conversion of CFs, characterized as elevated levels of α-SMA and Vimentin, with remarkable proliferation and migration in myocardial tissue. Mechanistically, our data indicate that such effects of OPN are mediated by nuclear translocation of YAP/TAZ via Hippo-YAP pathway, dependent of the membrane receptor integrin αVβ3. Overall, OPN plays significant roles in the phenotypic transition of CFs via integrin-Hippo-YAP axis, ultimately leading to MF. The findings highlight the novel mechanisms of OPN triggering MF and would offer an early marker and potential targets for the prevention and treatment of MF.
{"title":"Osteopontin aggravates myocardial fibrosis by promoting phenotypic transition of cardiac fibroblasts via Hippo-YAP pathway","authors":"Chen Liu , Wentao Liu , Yuan Wang , Chengzhi Jiang , Sheng Chen , Qianqian Huang , Xiaowei Xiong , Li Wang , Guohua Zeng , Qiren Huang","doi":"10.1016/j.bbadis.2025.168150","DOIUrl":"10.1016/j.bbadis.2025.168150","url":null,"abstract":"<div><div>Osteopontin (OPN), a glycosylated protein ubiquitously in cellular matrix, exhibits a low expression in normal myocardial tissue but a high expression in fibrotic myocardial tissue. However, the action and mechanisms of OPN on the pathogenesis of myocardial fibrosis (MF) remain unclear. The purpose of the study is to investigate the action and mechanisms of OPN on the occurrence and development of MF, emphasizing abnormal activation of cardiac fibroblasts (CFs) and extracellular matrix (ECM) deposition. Both NIH-3T3 cells and C57BL/6 J mice were infected with OPN over-expression adenoviruses (Ad-<em>Spp1</em>). Cardiac function and fibrosis degree were evaluated in the presence and absence of angiotensin (AngII) (<em>in vitro</em>) or isoprenaline (ISO) (<em>in vivo</em>). Our data demonstrate that OPN over-expression results in myocardial injury and ECM accumulation under the physiological condition. Moreover, it exacerbates such effects under the pathological condition induced by AngII or ISO; in contrast, OPN knockdown attenuates the fibrotic response <em>in vitro</em> induced by AngII. Interestingly, OPN significantly promotes phenotypic conversion of CFs, characterized as elevated levels of α-SMA and Vimentin, with remarkable proliferation and migration in myocardial tissue. Mechanistically, our data indicate that such effects of OPN are mediated by nuclear translocation of YAP/TAZ <em>via</em> Hippo-YAP pathway, dependent of the membrane receptor integrin α<sub>V</sub>β<sub>3</sub>. Overall, OPN plays significant roles in the phenotypic transition of CFs <em>via</em> integrin-Hippo-YAP axis, ultimately leading to MF. The findings highlight the novel mechanisms of OPN triggering MF and would offer an early marker and potential targets for the prevention and treatment of MF.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168150"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145879980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-24DOI: 10.1016/j.bbadis.2025.168121
Xiao Wang , Yinong Chang , Yong Qian , Wei min Shan , Guang Chen , Xiao-wei Li , Jie-hao Zhou
Renal fibrosis is a hallmark of chronic kidney disease (CKD), with epithelial–mesenchymal transition (EMT) recognized as a key contributing process. Here, we identify nuclear receptor NR5A2 as an important regulator that promotes EMT in renal tubular epithelial cells through transcriptional activation of MMP25. NR5A2 expression was consistently elevated in human fibrotic kidneys, a unilateral ureteral obstruction (UUO) mouse model, and TGF-β1–treated HK-2 cells. Both siRNA-mediated knockdown and pharmacological inhibition with ML-180 attenuated EMT markers and fibrotic responses. Mechanistically, NR5A2 directly bound to the MMP25 promoter, as demonstrated by luciferase reporter assays, ChIP–qPCR, and molecular docking analysis, while MMP25 silencing counteracted NR5A2-driven EMT. These findings suggest that the NR5A2–MMP25 axis contributes to renal fibrogenesis and may represent a potential therapeutic target for CKD.
{"title":"NR5A2 promotes epithelial-to-mesenchymal transition in renal fibrosis by targeting MMP25 transcription","authors":"Xiao Wang , Yinong Chang , Yong Qian , Wei min Shan , Guang Chen , Xiao-wei Li , Jie-hao Zhou","doi":"10.1016/j.bbadis.2025.168121","DOIUrl":"10.1016/j.bbadis.2025.168121","url":null,"abstract":"<div><div>Renal fibrosis is a hallmark of chronic kidney disease (CKD), with epithelial–mesenchymal transition (EMT) recognized as a key contributing process. Here, we identify nuclear receptor NR5A2 as an important regulator that promotes EMT in renal tubular epithelial cells through transcriptional activation of MMP25. NR5A2 expression was consistently elevated in human fibrotic kidneys, a unilateral ureteral obstruction (UUO) mouse model, and TGF-β1–treated HK-2 cells. Both siRNA-mediated knockdown and pharmacological inhibition with ML-180 attenuated EMT markers and fibrotic responses. Mechanistically, NR5A2 directly bound to the MMP25 promoter, as demonstrated by luciferase reporter assays, ChIP–qPCR, and molecular docking analysis, while MMP25 silencing counteracted NR5A2-driven EMT. These findings suggest that the NR5A2–MMP25 axis contributes to renal fibrogenesis and may represent a potential therapeutic target for CKD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168121"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-01DOI: 10.1016/j.bbadis.2025.168129
Zongyao Fan , Bin Ni , Zheng Duan , Feng Ling , Junjie Zhang , Jiayin Sun , Hao Yu , Jie Xu , Zhengsen Chen , Baixin Shen , Jun Xue , Zhongqing Wei
Diabetic bladder dysfunction (DBD), a prevalent yet underexplored complication of diabetes, manifests as debilitating lower urinary tract symptoms (LUTS), such as urinary frequency, urgency, incontinence, and voiding difficulties, significantly impairing quality of life and increasing mortality risks. Current therapies predominantly focus on symptom management, vesicoureteral reflux prevention, and renal protection, with bladder epithelial dysfunction emerging as a crucial pathogenic factor. This study reported significant upregulation of fat mass and obesity-associated protein (FTO) alongside global N6-methyladenosine (m6A) hypomodification in bladder epithelial tissues from patients with DBD and experimental models. Cellular models further demonstrated that FTO accelerated DBD progression by exacerbating ferroptosis and inflammatory responses in bladder epithelial cells. Mechanistically, FTO drived insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)-dependent recognition of m6A-depleted nuclear factor erythroid 2-related factor 2 (NRF2) transcripts, destabilizing NRF2 mRNA and inhibiting protein expression, with NRF2 restoration demonstrating protective effects in DBD models. Additionally, diabetes-induced FTO overexpression was driven by p300-mediated H3K9 lactylation (H3K9la). These findings collectively identified the H3K9la/FTO/NRF2 axis as a central regulator of epithelial injury in DBD, unveiling novel therapeutic targets for this challenging condition.
{"title":"H3K9 lactylation drives FTO-mediated NRF2 suppression to exacerbate bladder epithelial ferroptosis and inflammation in diabetic bladder dysfunction","authors":"Zongyao Fan , Bin Ni , Zheng Duan , Feng Ling , Junjie Zhang , Jiayin Sun , Hao Yu , Jie Xu , Zhengsen Chen , Baixin Shen , Jun Xue , Zhongqing Wei","doi":"10.1016/j.bbadis.2025.168129","DOIUrl":"10.1016/j.bbadis.2025.168129","url":null,"abstract":"<div><div>Diabetic bladder dysfunction (DBD), a prevalent yet underexplored complication of diabetes, manifests as debilitating lower urinary tract symptoms (LUTS), such as urinary frequency, urgency, incontinence, and voiding difficulties, significantly impairing quality of life and increasing mortality risks. Current therapies predominantly focus on symptom management, vesicoureteral reflux prevention, and renal protection, with bladder epithelial dysfunction emerging as a crucial pathogenic factor. This study reported significant upregulation of fat mass and obesity-associated protein (FTO) alongside global N6-methyladenosine (m6A) hypomodification in bladder epithelial tissues from patients with DBD and experimental models. Cellular models further demonstrated that FTO accelerated DBD progression by exacerbating ferroptosis and inflammatory responses in bladder epithelial cells. Mechanistically, FTO drived insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)-dependent recognition of m6A-depleted nuclear factor erythroid 2-related factor 2 (NRF2) transcripts, destabilizing NRF2 mRNA and inhibiting protein expression, with NRF2 restoration demonstrating protective effects in DBD models. Additionally, diabetes-induced FTO overexpression was driven by p300-mediated H3K9 lactylation (H3K9la). These findings collectively identified the H3K9la/FTO/NRF2 axis as a central regulator of epithelial injury in DBD, unveiling novel therapeutic targets for this challenging condition.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168129"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-10DOI: 10.1016/j.bbadis.2025.168105
Congcong Geng , Junling Zhen , Na Zhu , Fangjian Wang , Rui Ji , Lei Sun , Huizhen Du , Shujun Yan , Ziyuan Zhong , Yufei Zang , Qian Wang
Targeted therapy, as an effective therapeutic strategy for the treatment of colorectal cancer (CRC), is still limited by its applicability to specific patient populations and drug resistance. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying the development of CRC and identify novel targeted biomarkers. CACNA2D3 encodes the α2δ3 subunit of calcium (Ca2+) channels, and recent studies have consistently demonstrated its potential as a tumor suppressor. MicroRNAs (miRNAs) act by binding to the 3'-UTR of mRNAs to inhibit the function of target genes. Currently, the underlying mechanisms of CACNA2D3 and its upstream miRNAs in CRC remain elusive. Our study revealed that CACNA2D3, which is expressed at low levels in CRC, inhibits CRC cell proliferation and promotes apoptosis by up-regulating intracellular Ca2+ and ROS levels and activating the mitochondrial apoptotic pathway. miR-27a-3p, whose expression level is significantly upregulated in CRC, is an upstream miRNA of CACNA2D3, and promote the progression of CRC by negatively regulating CACNA2D3.By exploring the mechanism of action of CACNA2D3 in colorectal cancer and identifying potential upstream microRNAs, we aim to provide a new strategy for targeted therapy for CRC.
{"title":"miR-27a-3p targets CACNA2D3 to promote colorectal cancer progression via the Ca2+/ROS/mitochondrial apoptotic pathway","authors":"Congcong Geng , Junling Zhen , Na Zhu , Fangjian Wang , Rui Ji , Lei Sun , Huizhen Du , Shujun Yan , Ziyuan Zhong , Yufei Zang , Qian Wang","doi":"10.1016/j.bbadis.2025.168105","DOIUrl":"10.1016/j.bbadis.2025.168105","url":null,"abstract":"<div><div>Targeted therapy, as an effective therapeutic strategy for the treatment of colorectal cancer (CRC), is still limited by its applicability to specific patient populations and drug resistance. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying the development of CRC and identify novel targeted biomarkers. CACNA2D3 encodes the α2δ3 subunit of calcium (Ca<sup>2+</sup>) channels, and recent studies have consistently demonstrated its potential as a tumor suppressor. MicroRNAs (miRNAs) act by binding to the 3'-UTR of mRNAs to inhibit the function of target genes. Currently, the underlying mechanisms of CACNA2D3 and its upstream miRNAs in CRC remain elusive. Our study revealed that CACNA2D3, which is expressed at low levels in CRC, inhibits CRC cell proliferation and promotes apoptosis by up-regulating intracellular Ca<sup>2+</sup> and ROS levels and activating the mitochondrial apoptotic pathway. miR-27a-3p, whose expression level is significantly upregulated in CRC, is an upstream miRNA of CACNA2D3, and promote the progression of CRC by negatively regulating CACNA2D3.By exploring the mechanism of action of CACNA2D3 in colorectal cancer and identifying potential upstream microRNAs, we aim to provide a new strategy for targeted therapy for CRC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168105"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-05-29DOI: 10.1016/j.bbadis.2025.167939
Haitao Li , Yuxuan Ou , Lifu Chen , Yong Li , Wei Wang , Jian Wang
Abnormal mechanical loading, which can lead to articular cartilage damage, is a significant contributor to the onset of osteoarthritis (OA). Articular cartilage superficial layer cells are among the first cells to respond to changes in the mechanical environment and are highly sensitive to mechanical stimuli. This study aimed to investigate the effects of high fluid shear stress on the articular cartilage superficial layer cells and the underlying mechanisms. We found that high fluid shear stress of 20 dyne/cm2 induces inflammation and promotes catabolic processes in these cells. Short-term high fluid shear stress has a protective effect, but its efficacy varies with time. YAP plays a crucial role in mediating the effects of high fluid shear stress and may represent a potential therapeutic target for early-stage osteoarthritis. The study also established osteoarthritis models using anterior cruciate ligament transection (ACLT) or injection of sodium iodoacetate (MIA) to further confirm the findings.
{"title":"High fluid shear stress induces Hippo/YAP pathway in articular cartilage superficial layer cells: A potential mechanistic link to osteoarthritis","authors":"Haitao Li , Yuxuan Ou , Lifu Chen , Yong Li , Wei Wang , Jian Wang","doi":"10.1016/j.bbadis.2025.167939","DOIUrl":"10.1016/j.bbadis.2025.167939","url":null,"abstract":"<div><div>Abnormal mechanical loading, which can lead to articular cartilage damage, is a significant contributor to the onset of osteoarthritis (OA). Articular cartilage superficial layer cells are among the first cells to respond to changes in the mechanical environment and are highly sensitive to mechanical stimuli. This study aimed to investigate the effects of high fluid shear stress on the articular cartilage superficial layer cells and the underlying mechanisms. We found that high fluid shear stress of 20 dyne/cm<sup>2</sup> induces inflammation and promotes catabolic processes in these cells. Short-term high fluid shear stress has a protective effect, but its efficacy varies with time. YAP plays a crucial role in mediating the effects of high fluid shear stress and may represent a potential therapeutic target for early-stage osteoarthritis. The study also established osteoarthritis models using anterior cruciate ligament transection (ACLT) or injection of sodium iodoacetate (MIA) to further confirm the findings.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 167939"},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-10-30DOI: 10.1016/j.bbadis.2025.168097
Chongyang Wu , Wenzhe Si , Hanxiao Li , Jie Sheng , Fei Pei , Xujun Liu , Xinping Su , Ying Wang , Cihang Liu , Yihua Zhang , Bin Jiang , Wengong Wang , Xia Yi
PRDM15, a member of the PRDM family, is critically involved in embryonic development, cell differentiation, and tumorigenesis. However, its specific regulatory mechanisms in tumorigenesis remain poorly understood. This study demonstrates that PRDM15 is significantly upregulated in colorectal cancer (CRC) tissues and positively correlates with advanced pathological staging. Knockdown of PRDM15 inhibits p53-dependent cell proliferation by arresting cell cycle progression and promoting apoptosis, thereby suppressing colorectal carcinogenesis both in vitro and in vivo. Furthermore, PRDM15 depletion enhances the sensitivity of HCT116 cells to the chemotherapeutic agent 5-Fluorouracil (5-FU). Mechanistically, PRDM15 functions as a novel negative regulator of p53, exerting its oncogenic effects by transcriptionally downregulating USP10, which in turn destabilizes p53. These findings underscore the critical role of the PRDM15-USP10-p53 axis in CRC progression, offering new insights into the molecular mechanisms driving CRC and identifying potential therapeutic targets for intervention.
{"title":"PRDM15 promotes colorectal carcinogenesis by transcriptionally repressing USP10 to destabilize p53","authors":"Chongyang Wu , Wenzhe Si , Hanxiao Li , Jie Sheng , Fei Pei , Xujun Liu , Xinping Su , Ying Wang , Cihang Liu , Yihua Zhang , Bin Jiang , Wengong Wang , Xia Yi","doi":"10.1016/j.bbadis.2025.168097","DOIUrl":"10.1016/j.bbadis.2025.168097","url":null,"abstract":"<div><div>PRDM15, a member of the PRDM family, is critically involved in embryonic development, cell differentiation, and tumorigenesis. However, its specific regulatory mechanisms in tumorigenesis remain poorly understood. This study demonstrates that PRDM15 is significantly upregulated in colorectal cancer (CRC) tissues and positively correlates with advanced pathological staging. Knockdown of PRDM15 inhibits p53-dependent cell proliferation by arresting cell cycle progression and promoting apoptosis, thereby suppressing colorectal carcinogenesis both <em>in vitro</em> and <em>in vivo</em>. Furthermore, PRDM15 depletion enhances the sensitivity of HCT116 cells to the chemotherapeutic agent 5-Fluorouracil (5-FU). Mechanistically, PRDM15 functions as a novel negative regulator of p53, exerting its oncogenic effects by transcriptionally downregulating USP10, which in turn destabilizes p53. These findings underscore the critical role of the PRDM15-USP10-p53 axis in CRC progression, offering new insights into the molecular mechanisms driving CRC and identifying potential therapeutic targets for intervention.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168097"},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-11-01DOI: 10.1016/j.bbadis.2025.168099
Xinru Xi , Huiwen Chen , Haoyu Ji , Tingfang Xiao , Zhihe Liu , Jingyi Chen , Xiangting Ge , Yali Zhang , Xiaona Zhu
Background
Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is a chronic inflammatory respiratory disease characterized by airflow limitation. Myeloid differentiation protein 2 (MD2), an important accessory protein of toll like receptor 4 (TLR4), plays a crucial role in mediating lung disease pathogenesis, however, its functional contribution to COPD progression remains poorly understood.
Methods
In vivo, MD2 knockout mice were utilized to establish cigarette smoke -induced COPD or combined with lipopolysaccharide-induced acute exacerbation COPD (AECOPD). L6H21 was used as a pharmacological inhibitor of MD2. In vitro, cellular model was established by stimulating human bronchial epithelial cells (BEAS-2B) with cigarette smoke extract (CSE). Immunoprecipitation assay was used to elucidate MD2/TLR4/MyD88 complex formation. The changes of inflammation and ferroptosis-related indicators were detected by several molecular biology techniques.
Results
MD2 expression was upregulated in COPD patients and mouse lungs. Genetic knockout of MD2 significantly alleviated airway inflammation and pulmonary ferroptosis in COPD mice. In vitro studies demonstrated that MD2 silencing or L6H21 mitigated CSE-induced NF-κB activation, pro-inflammatory gene expression, and changes in ferroptosis-related markers in BEAS-2B cells. Mechanistically, MD2 could form complex with TLR4/MyD88 upon CSE stimulation in BEAS-2B cells. Additionally, MD2 knockout or L6H21 significantly attenuated airway inflammation and lung ferroptosis in AECOPD mice.
Conclusion
These results indicated that MD2 promotes ferroptosis in airway epithelial cells by forming a complex with TLR4/MyD88, activating NF-κB-mediated inflammatory responses to exacerbate COPD pathogenesis. These findings identify MD2 as a potential therapeutic target and provide novel insights for COPD intervention strategies.
背景：慢性阻塞性肺疾病（COPD）是一种以气流限制为特征的慢性炎症性呼吸系统疾病，是全球第三大死亡原因。髓样分化蛋白2 （Myeloid differentiation protein 2, MD2）是toll样受体4 （toll like receptor 4, TLR4）的重要辅助蛋白，在介导肺部疾病发病机制中起着至关重要的作用，然而，其在COPD进展中的功能贡献尚不清楚。方法：在体内，利用MD2基因敲除小鼠建立香烟烟雾诱导的COPD或合并脂多糖诱导的急性加重性COPD （AECOPD）。L6H21作为MD2的药理学抑制剂。体外用香烟烟雾提取物（CSE）刺激人支气管上皮细胞（BEAS-2B）建立细胞模型。免疫沉淀法阐明MD2/TLR4/MyD88复合物的形成。应用分子生物学技术检测炎症及嗜铁相关指标的变化。结果：MD2在COPD患者和小鼠肺中表达上调。基因敲除MD2可显著减轻COPD小鼠气道炎症和肺铁下垂。体外研究表明，MD2沉默或L6H21可减轻cse诱导的BEAS-2B细胞中NF-κB活化、促炎基因表达和铁中毒相关标志物的变化。机制上，在BEAS-2B细胞中，MD2在CSE刺激下可与TLR4/MyD88形成复合物。此外，MD2敲除或L6H21可显著减轻AECOPD小鼠的气道炎症和肺铁下垂。结论：上述结果提示MD2通过与TLR4/MyD88形成复合物，激活NF-κ b介导的炎症反应，促进气道上皮细胞铁下沉，加重COPD发病。这些发现确定MD2是潜在的治疗靶点，并为COPD干预策略提供了新的见解。
{"title":"MD2 mediates COPD pathogenesis by inducing airway inflammation and ferroptosis through the TLR4/MyD88 pathway","authors":"Xinru Xi , Huiwen Chen , Haoyu Ji , Tingfang Xiao , Zhihe Liu , Jingyi Chen , Xiangting Ge , Yali Zhang , Xiaona Zhu","doi":"10.1016/j.bbadis.2025.168099","DOIUrl":"10.1016/j.bbadis.2025.168099","url":null,"abstract":"<div><h3>Background</h3><div>Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is a chronic inflammatory respiratory disease characterized by airflow limitation. Myeloid differentiation protein 2 (MD2), an important accessory protein of toll like receptor 4 (TLR4), plays a crucial role in mediating lung disease pathogenesis, however, its functional contribution to COPD progression remains poorly understood.</div></div><div><h3>Methods</h3><div>In vivo, MD2 knockout mice were utilized to establish cigarette smoke -induced COPD or combined with lipopolysaccharide-induced acute exacerbation COPD (AECOPD). L6H21 was used as a pharmacological inhibitor of MD2. In vitro, cellular model was established by stimulating human bronchial epithelial cells (BEAS-2B) with cigarette smoke extract (CSE). Immunoprecipitation assay was used to elucidate MD2/TLR4/MyD88 complex formation. The changes of inflammation and ferroptosis-related indicators were detected by several molecular biology techniques.</div></div><div><h3>Results</h3><div>MD2 expression was upregulated in COPD patients and mouse lungs. Genetic knockout of MD2 significantly alleviated airway inflammation and pulmonary ferroptosis in COPD mice. In vitro studies demonstrated that MD2 silencing or L6H21 mitigated CSE-induced NF-κB activation, pro-inflammatory gene expression, and changes in ferroptosis-related markers in BEAS-2B cells. Mechanistically, MD2 could form complex with TLR4/MyD88 upon CSE stimulation in BEAS-2B cells. Additionally, MD2 knockout or L6H21 significantly attenuated airway inflammation and lung ferroptosis in AECOPD mice.</div></div><div><h3>Conclusion</h3><div>These results indicated that MD2 promotes ferroptosis in airway epithelial cells by forming a complex with TLR4/MyD88, activating NF-κB-mediated inflammatory responses to exacerbate COPD pathogenesis. These findings identify MD2 as a potential therapeutic target and provide novel insights for COPD intervention strategies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168099"},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metabolic dysfunction-associated steatohepatitis (MASH) has received increasing attention because of the increase in the number of affected patients. However, the mechanism underlying its onset is complicated and has not been completely elucidated. We recently reported increased Pin1 expression in the liver of patients with MASH. Therefore, we aimed to investigate the role of hepatocyte Pin1 in MASH development.
Hepatocyte-specific Pin1-knockout (H-Pin1 KO) and Pin1-flox (WT) littermates were fed a high-fat, high-cholesterol diet for 16 weeks. The WT mice showed remarkable obesity, steatosis, liver fibrosis, and liver injury. Conversely, the H-Pin1 KO mice exhibited mild symptoms. One explanation of these phenomena was that Pin1 interacted with acetyl CoA carboxylase (ACC) and increased its expressions in the liver without affecting its phosphorylation. In addition, RNA sequencing analysis revealed that Pin1 deficiency in hepatocytes promoted the pathway of fatty acid degradation, including peroxisome proliferator-activated receptor alpha (PPARα) signaling in the livers. Indeed, we found that Pin1 silencing upregulated the expressions of PPARα-target genes in vitro and in vivo. Consistent with these results, Pin1 deficiency in hepatocytes elevated serum fibroblast growth factor 21 (FGF21) concentrations, which is a representative target of PPARα, and serum beta-hydroxybutyrate produced by fatty acid oxidation. Importantly, we also reveal that Pin1 binds with PPARα, downregulating its transcription without affecting its expression levels or translocation.
Taken together, our findings indicate that Pin1 acts as a critical mediator of MASH development by regulating both PPARα and ACC1. Hence, developing selective Pin1 inhibitors may be beneficial for treating MASH.
{"title":"Pin1 mediates metabolic dysfunction-associated steatohepatitis in mice fed high-fat, high-cholesterol diet by regulating both PPARα and acetyl CoA carboxylase","authors":"Yusuke Nakatsu , Tomomi Sano , Mikako Nakanishi , Yasuka Matsunaga , Machi Kanna , Takashi Kanematsu , Tomoichiro Asano","doi":"10.1016/j.bbadis.2025.168087","DOIUrl":"10.1016/j.bbadis.2025.168087","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) has received increasing attention because of the increase in the number of affected patients. However, the mechanism underlying its onset is complicated and has not been completely elucidated. We recently reported increased Pin1 expression in the liver of patients with MASH. Therefore, we aimed to investigate the role of hepatocyte Pin1 in MASH development.</div><div>Hepatocyte-specific Pin1-knockout (H-Pin1 KO) and Pin1-flox (WT) littermates were fed a high-fat, high-cholesterol diet for 16 weeks. The WT mice showed remarkable obesity, steatosis, liver fibrosis, and liver injury. Conversely, the H-Pin1 KO mice exhibited mild symptoms. One explanation of these phenomena was that Pin1 interacted with acetyl CoA carboxylase (ACC) and increased its expressions in the liver without affecting its phosphorylation. In addition, RNA sequencing analysis revealed that Pin1 deficiency in hepatocytes promoted the pathway of fatty acid degradation, including peroxisome proliferator-activated receptor alpha (PPARα) signaling in the livers. Indeed, we found that <em>Pin1</em> silencing upregulated the expressions of PPARα-target genes in vitro and in vivo. Consistent with these results, Pin1 deficiency in hepatocytes elevated serum fibroblast growth factor 21 (FGF21) concentrations, which is a representative target of PPARα, and serum beta-hydroxybutyrate produced by fatty acid oxidation. Importantly, we also reveal that Pin1 binds with PPARα, downregulating its transcription without affecting its expression levels or translocation.</div><div>Taken together, our findings indicate that Pin1 acts as a critical mediator of MASH development by regulating both PPARα and ACC1. Hence, developing selective Pin1 inhibitors may be beneficial for treating MASH.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 2","pages":"Article 168087"},"PeriodicalIF":4.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145369126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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