The hallmark of aerobic glycolysis in cancer progression is well-established, yet its specific role in pancreatic cancer (PC) remains elusive. Here, we reported that TFAP2A is upregulated in PC tissues, and elevated TFAP2A expression correlates with poor prognosis in patients. Functionally, we found that TFAP2A boosted the viability, invasion, and migration of PC cells in vitro, whereas TFAP2A depletion restrained tumor growth in vivo. Moreover, TFAP2A knockdown hindered aerobic glycolysis of PC cells. Further investigation revealed that TFAP2A deletion decreased LDHA expression in PC cells. LDHA overexpression counteracted the impacts of TFAP2A deletion on cell viability, migration, invasion, and aerobic glycolysis. Mechanistically, TFAP2A was directly bound to the promoter of IGF2BP2, upregulating its expression. Additionally, IGF2BP2 was found to bind to the m6A site in LDHA mRNA, thereby enhancing its stability. Overall, TFAP2A facilitated aerobic glycolysis and PC progression via IGF2BP2-mediated stabilization of LDHA mRNA, providing novel insights for PC therapy.
{"title":"TFAP2A facilitates aerobic glycolysis and metastasis of pancreatic cancer via IGF2BP2-mediated LDHA m<sup>6</sup>A modification.","authors":"Zhiying Xu, Xingyang Zhong, Zhishi Yang, Zhuangzhi Cong, Lianwei Peng, Qifei Zou","doi":"10.1016/j.prp.2026.156387","DOIUrl":"https://doi.org/10.1016/j.prp.2026.156387","url":null,"abstract":"<p><p>The hallmark of aerobic glycolysis in cancer progression is well-established, yet its specific role in pancreatic cancer (PC) remains elusive. Here, we reported that TFAP2A is upregulated in PC tissues, and elevated TFAP2A expression correlates with poor prognosis in patients. Functionally, we found that TFAP2A boosted the viability, invasion, and migration of PC cells in vitro, whereas TFAP2A depletion restrained tumor growth in vivo. Moreover, TFAP2A knockdown hindered aerobic glycolysis of PC cells. Further investigation revealed that TFAP2A deletion decreased LDHA expression in PC cells. LDHA overexpression counteracted the impacts of TFAP2A deletion on cell viability, migration, invasion, and aerobic glycolysis. Mechanistically, TFAP2A was directly bound to the promoter of IGF2BP2, upregulating its expression. Additionally, IGF2BP2 was found to bind to the m<sup>6</sup>A site in LDHA mRNA, thereby enhancing its stability. Overall, TFAP2A facilitated aerobic glycolysis and PC progression via IGF2BP2-mediated stabilization of LDHA mRNA, providing novel insights for PC therapy.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"280 ","pages":"156387"},"PeriodicalIF":3.2,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C3aR1 (complement component 3a receptor 1), a key member of the complement system, belongs to the G protein-coupled receptor (GPCR) family. It plays an indispensable role in physiological processes such as immunomodulation, inflammatory response, and cellular signaling through specific binding to its ligand C3a. In recent years, numerous studies have demonstrated the significant role of C3aR1 in the pathogenesis of various diseases, including inflammatory diseases, cardiovascular diseases, and tumors. Particularly within the tumor microenvironment (TME), C3aR1 can promote tumor progression by regulating key processes such as immune evasion, angiogenesis, and cell invasion. This review provides a comprehensive and in-depth overview of the structure and function of C3aR1, its mechanisms of action in various diseases, and its potential as a therapeutic target.
{"title":"The multifaceted roles of G protein-coupled receptor C3aR1 in disease: From immunomodulation to cancer progression.","authors":"Jiayao Cui, Fangyu Shen, Chenmiao Zhang, Chaojie Fu, Jian Zhu, Ting Zhuang","doi":"10.1016/j.prp.2026.156386","DOIUrl":"https://doi.org/10.1016/j.prp.2026.156386","url":null,"abstract":"<p><p>C3aR1 (complement component 3a receptor 1), a key member of the complement system, belongs to the G protein-coupled receptor (GPCR) family. It plays an indispensable role in physiological processes such as immunomodulation, inflammatory response, and cellular signaling through specific binding to its ligand C3a. In recent years, numerous studies have demonstrated the significant role of C3aR1 in the pathogenesis of various diseases, including inflammatory diseases, cardiovascular diseases, and tumors. Particularly within the tumor microenvironment (TME), C3aR1 can promote tumor progression by regulating key processes such as immune evasion, angiogenesis, and cell invasion. This review provides a comprehensive and in-depth overview of the structure and function of C3aR1, its mechanisms of action in various diseases, and its potential as a therapeutic target.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"280 ","pages":"156386"},"PeriodicalIF":3.2,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146126069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1016/j.prp.2026.156383
Wensha Nie, Siyi Wang, Yongze Liu, Jiawu Yang, Qinglang Dai, Yuan Liao, Feng Li
Background: Acute lung injury (ALI) has high incidence and mortality rates among patients. Studies have shown that USP18 is widely involved in the immunomodulatory process and that macrophage polarization plays a key role in the progression of ALI. This study aimed to explore the potential molecular mechanism through which USP18 promotes M2 macrophage polarization and alleviates ALI.
Methods: RAW264.7 cell injury and ALI mouse animal models were established by LPS induction. Lung tissue injury was evaluated by HE staining. Protein expression was evaluated by Western blotting, immunofluorescence and ELISA. Mitochondrial function was evaluated using JC-1 staining and ROS and ATP assays.
Results: USP18 is highly expressed in the lung tissues of ALI model mice. Overexpression of USP18 significantly alleviated pathological injury to lung tissue in mice with LPS-induced ALI; reduced MPO activity, the number of inflammatory cells and the protein content in BALF; and decreased the levels of the M1 markers iNOS, CD80, and CD86 and the proinflammatory factors IL-1β, IL-6, and TNF-α. Moreover, the expression of the M2 markers Arg1, CD206, and CD163 and the anti-inflammatory factor IL-10 increased, thereby inhibiting the M1 polarization of macrophages induced by LPS. Furthermore, USP18 markedly increased mitochondrial ATP levels and transmembrane potential, reduced ROS levels, and alleviated mitochondrial dysfunction in macrophages. Further studies have shown that USP18 stabilizes the expression of PKM2 through deubiquitination, while knockdown of PKM2 weakens the ability of USP18 to improve mitochondrial function and inhibit LPS-induced M1 polarization in macrophages.
Conclusion: USP18 stabilizes the expression of PKM2 via deubiquitination, thereby enhancing mitochondrial homeostasis and promoting M2 macrophage polarization to alleviate ALI.
{"title":"USP18 improves mitochondrial homeostasis by stabilizing PKM2 and promoting M2 polarization in macrophages to relieve acute lung injury.","authors":"Wensha Nie, Siyi Wang, Yongze Liu, Jiawu Yang, Qinglang Dai, Yuan Liao, Feng Li","doi":"10.1016/j.prp.2026.156383","DOIUrl":"https://doi.org/10.1016/j.prp.2026.156383","url":null,"abstract":"<p><strong>Background: </strong>Acute lung injury (ALI) has high incidence and mortality rates among patients. Studies have shown that USP18 is widely involved in the immunomodulatory process and that macrophage polarization plays a key role in the progression of ALI. This study aimed to explore the potential molecular mechanism through which USP18 promotes M2 macrophage polarization and alleviates ALI.</p><p><strong>Methods: </strong>RAW264.7 cell injury and ALI mouse animal models were established by LPS induction. Lung tissue injury was evaluated by HE staining. Protein expression was evaluated by Western blotting, immunofluorescence and ELISA. Mitochondrial function was evaluated using JC-1 staining and ROS and ATP assays.</p><p><strong>Results: </strong>USP18 is highly expressed in the lung tissues of ALI model mice. Overexpression of USP18 significantly alleviated pathological injury to lung tissue in mice with LPS-induced ALI; reduced MPO activity, the number of inflammatory cells and the protein content in BALF; and decreased the levels of the M1 markers iNOS, CD80, and CD86 and the proinflammatory factors IL-1β, IL-6, and TNF-α. Moreover, the expression of the M2 markers Arg1, CD206, and CD163 and the anti-inflammatory factor IL-10 increased, thereby inhibiting the M1 polarization of macrophages induced by LPS. Furthermore, USP18 markedly increased mitochondrial ATP levels and transmembrane potential, reduced ROS levels, and alleviated mitochondrial dysfunction in macrophages. Further studies have shown that USP18 stabilizes the expression of PKM2 through deubiquitination, while knockdown of PKM2 weakens the ability of USP18 to improve mitochondrial function and inhibit LPS-induced M1 polarization in macrophages.</p><p><strong>Conclusion: </strong>USP18 stabilizes the expression of PKM2 via deubiquitination, thereby enhancing mitochondrial homeostasis and promoting M2 macrophage polarization to alleviate ALI.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"280 ","pages":"156383"},"PeriodicalIF":3.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1016/j.prp.2026.156385
Yuhang Wang , Han Zhang , Jiaqi Liu , Rimei Lin , Yingyu Huang , Xinrui Liu , Yunqi Dong , Hongkui Lu , Yutong Wei , Haoze Lv , Xinyu Liu , Cong Sun
Background and objectives
Sepsis-Induced Myocardial Injury (SIMI) poses a serious threat to patients' lives. Although curcumin (Cur) has potential therapeutic effects on SIMI, its clinical application is hindered by the limitation of low bioavailability. The emergence of nanodelivery systems provides novel strategies to address this issue. This study aimed to investigate the therapeutic effects of curcumin nanoparticles (Cur-NPs) on septic myocarditis (SIMI) and its potential molecular mechanisms.
Materials and methods
Cur-NPs were prepared using the ion cross-linking method, and a septicemia mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS). Immunofluorescence, Western blot (WB), real-time quantitative PCR (RT-qPCR), and other molecular biology techniques were employed to systematically explore the molecular mechanisms underlying the therapeutic effects of Cur-NPs on SIMI.
Results
Cur-NPs significantly alleviated myocardial tissue damage induced by septicemia and effectively mitigated inflammatory responses and mitochondrial damage. Mechanistic studies revealed that Cur-NPs upregulated the expression levels of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), Heme Oxygenase-1 (HO-1), Solute Carrier Family 7 Member 11 (SLC7A11), Glutathione Peroxidase 4 (GPX4), Ferroptosis-suppressor-protein 1 (FSP1), and ferritin, while downregulating the expression of Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), LysoPHosPHatidylcholine Acyltransferase 3 (LPCAT3), and 4-hydroxynonenal (4-HNE), thereby inhibiting ferroptosis in cardiomyocytes.
Conclusions
Cur-NPs can effectively alleviate SIMI by dual regulation of the Nrf2/HO-1/xCT/GPX4 pathway and the ACSL4/LPCAT3 pathway, providing a promising new approach for the clinical treatment of SIMI.
{"title":"Curcumin nanoparticles attenuate sepsis-induced myocardial injury by modulating the Nrf2/HO-1/SLC7A11/GPX4 and ACSL4/LPCAT3 pathways","authors":"Yuhang Wang , Han Zhang , Jiaqi Liu , Rimei Lin , Yingyu Huang , Xinrui Liu , Yunqi Dong , Hongkui Lu , Yutong Wei , Haoze Lv , Xinyu Liu , Cong Sun","doi":"10.1016/j.prp.2026.156385","DOIUrl":"10.1016/j.prp.2026.156385","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Sepsis-Induced Myocardial Injury (SIMI) poses a serious threat to patients' lives. Although curcumin (Cur) has potential therapeutic effects on SIMI, its clinical application is hindered by the limitation of low bioavailability. The emergence of nanodelivery systems provides novel strategies to address this issue. This study aimed to investigate the therapeutic effects of curcumin nanoparticles (Cur-NPs) on septic myocarditis (SIMI) and its potential molecular mechanisms.</div></div><div><h3>Materials and methods</h3><div>Cur-NPs were prepared using the ion cross-linking method, and a septicemia mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS). Immunofluorescence, Western blot (WB), real-time quantitative PCR (RT-qPCR), and other molecular biology techniques were employed to systematically explore the molecular mechanisms underlying the therapeutic effects of Cur-NPs on SIMI.</div></div><div><h3>Results</h3><div>Cur-NPs significantly alleviated myocardial tissue damage induced by septicemia and effectively mitigated inflammatory responses and mitochondrial damage. Mechanistic studies revealed that Cur-NPs upregulated the expression levels of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), Heme Oxygenase-1 (HO-1), Solute Carrier Family 7 Member 11 (SLC7A11), Glutathione Peroxidase 4 (GPX4), Ferroptosis-suppressor-protein 1 (FSP1), and ferritin, while downregulating the expression of Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), LysoPHosPHatidylcholine Acyltransferase 3 (LPCAT3), and 4-hydroxynonenal (4-HNE), thereby inhibiting ferroptosis in cardiomyocytes.</div></div><div><h3>Conclusions</h3><div>Cur-NPs can effectively alleviate SIMI by dual regulation of the Nrf2/HO-1/xCT/GPX4 pathway and the ACSL4/LPCAT3 pathway, providing a promising new approach for the clinical treatment of SIMI.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"280 ","pages":"Article 156385"},"PeriodicalIF":3.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-29DOI: 10.1016/j.prp.2026.156382
Ru Nie , Yunlong Duan , Xiaoting Cao , Mingquan Pang , Zhixin Wang , Haining Fan
Hepatic ischemia–reperfusion injury (HIRI) remains a major clinical challenge in liver surgery, transplantation, and trauma, contributing to graft dysfunction and increased morbidity. This review summarizes the complex pathophysiology of HIRI, including metabolic derangements during ischemia, bursts of oxidative stress on reperfusion, and sterile inflammation driven by reactive oxygen species (ROS) and immune-cell activation. It also examines regulated cell death pathways—apoptosis, pyroptosis, necroptosis, and ferroptosis—that interact to create self-reinforcing cycles and further amplify tissue injury.Building on these mechanistic insights, the review highlights emerging therapeutic strategies centered on mesenchymal stem cells (MSCs) and MSC-derived products, including extracellular vesicles (EVs), exosomes, and conditioned medium. MSCs confer protection through immunomodulatory effects, such as promoting macrophage polarization toward anti-inflammatory phenotypes, as well as through cytoprotective mechanisms including antioxidant secretion and mitochondrial transfer. In addition, MSCs support tissue repair by enhancing regenerative responses. Preclinical studies consistently show that MSC-based interventions reduce oxidative stress, inflammation, and cell death. Early clinical trials in liver transplantation further suggest that MSC therapy is safe and may reduce ischemia-associated complications.Finally, this review discusses key translational barriers, including inefficient homing, donor-to-donor variability, and the need for standardized manufacturing and potency assessment. Future directions include MSC preconditioning, EV engineering, and combination approaches with machine perfusion technologies. By integrating mechanistic understanding with therapeutic advances, this review underscores the potential of MSC-based therapies to reshape HIRI management and highlights broader opportunities for regenerative medicine in organ injury.
{"title":"Pathological mechanisms of hepatic ischemia-reperfusion injury and stem cell–based therapeutic strategies: Mechanistic insights and translational perspectives","authors":"Ru Nie , Yunlong Duan , Xiaoting Cao , Mingquan Pang , Zhixin Wang , Haining Fan","doi":"10.1016/j.prp.2026.156382","DOIUrl":"10.1016/j.prp.2026.156382","url":null,"abstract":"<div><div>Hepatic ischemia–reperfusion injury (HIRI) remains a major clinical challenge in liver surgery, transplantation, and trauma, contributing to graft dysfunction and increased morbidity. This review summarizes the complex pathophysiology of HIRI, including metabolic derangements during ischemia, bursts of oxidative stress on reperfusion, and sterile inflammation driven by reactive oxygen species (ROS) and immune-cell activation. It also examines regulated cell death pathways—apoptosis, pyroptosis, necroptosis, and ferroptosis—that interact to create self-reinforcing cycles and further amplify tissue injury.Building on these mechanistic insights, the review highlights emerging therapeutic strategies centered on mesenchymal stem cells (MSCs) and MSC-derived products, including extracellular vesicles (EVs), exosomes, and conditioned medium. MSCs confer protection through immunomodulatory effects, such as promoting macrophage polarization toward anti-inflammatory phenotypes, as well as through cytoprotective mechanisms including antioxidant secretion and mitochondrial transfer. In addition, MSCs support tissue repair by enhancing regenerative responses. Preclinical studies consistently show that MSC-based interventions reduce oxidative stress, inflammation, and cell death. Early clinical trials in liver transplantation further suggest that MSC therapy is safe and may reduce ischemia-associated complications.Finally, this review discusses key translational barriers, including inefficient homing, donor-to-donor variability, and the need for standardized manufacturing and potency assessment. Future directions include MSC preconditioning, EV engineering, and combination approaches with machine perfusion technologies. By integrating mechanistic understanding with therapeutic advances, this review underscores the potential of MSC-based therapies to reshape HIRI management and highlights broader opportunities for regenerative medicine in organ injury.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"280 ","pages":"Article 156382"},"PeriodicalIF":3.2,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1016/j.prp.2026.156379
Jialong Zhang , Lexing Yang , Jun He , Weiyi Li, Hongzhi Wang, Chaozhao Liang
Previous studies suggested the link between sleep deprivation and prostate cancer, but its impact on disease progression is unclear. Moreover, clarifying this relationship could offer insights into prostate cancer mechanisms and potential treatments. In the present study, questionnaire and sleep monitoring of prostate cancer patients indicate that worse sleep quality correlates with higher Gleason scores. Subsequently, to study the effects of sleep deprivation in vivo, a sleep deprivation mouse model was established. Our findings show that sleep deprivation could accelerate tumor growth. Then, we performed transcriptome sequencing to infer the underlying mechanism. RNA sequencing found inflammation related pathways were activated in the sleep deprivation model. Moreover, we identified CXCL13 as a key mediator of sleep deprivation induced prostate progression. And inhibition of CXCR5, the receptor of CXCL13, reduced its tumor promoting effects. Molecular mechanism studies showed that CXCL13 enhanced cancer cell proliferation via activating JNK signaling pathway. In summary, our findings suggest that sleep deprivation may accelerate prostate cancer progression by activating the CXCL13/CXCR5/JNK signaling axis. These results provide preliminary insights into a potential therapeutic direction.
{"title":"The role of sleep deprivation in prostate cancer and a preliminary exploration of its mechanisms","authors":"Jialong Zhang , Lexing Yang , Jun He , Weiyi Li, Hongzhi Wang, Chaozhao Liang","doi":"10.1016/j.prp.2026.156379","DOIUrl":"10.1016/j.prp.2026.156379","url":null,"abstract":"<div><div>Previous studies suggested the link between sleep deprivation and prostate cancer, but its impact on disease progression is unclear. Moreover, clarifying this relationship could offer insights into prostate cancer mechanisms and potential treatments. In the present study, questionnaire and sleep monitoring of prostate cancer patients indicate that worse sleep quality correlates with higher Gleason scores. Subsequently, to study the effects of sleep deprivation in vivo, a sleep deprivation mouse model was established. Our findings show that sleep deprivation could accelerate tumor growth. Then, we performed transcriptome sequencing to infer the underlying mechanism. RNA sequencing found inflammation related pathways were activated in the sleep deprivation model. Moreover, we identified CXCL13 as a key mediator of sleep deprivation induced prostate progression. And inhibition of CXCR5, the receptor of CXCL13, reduced its tumor promoting effects. Molecular mechanism studies showed that CXCL13 enhanced cancer cell proliferation via activating JNK signaling pathway. In summary, our findings suggest that sleep deprivation may accelerate prostate cancer progression by activating the CXCL13/CXCR5/JNK signaling axis. These results provide preliminary insights into a potential therapeutic direction.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"280 ","pages":"Article 156379"},"PeriodicalIF":3.2,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146070985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1016/j.prp.2026.156381
Roshni Bibi, Arunika Koley, Koustav Sarkar
Background
Cancer remains one of the most pressing global health challenges, with conventional treatments such as chemotherapy and radiotherapy constrained by modest efficacy and severe long‑term adverse effects. Exosomes—nano‑sized extracellular vesicles (30–150 nm) secreted by diverse cell types—have emerged as promising candidates for cancer diagnosis and therapy due to their inherent biocompatibility, low immunogenicity, and ability to cross biological barriers.
Methods
A comprehensive review of recent literature was conducted to summarize advancements in exosome biology, isolation techniques, and engineering strategies relevant to cancer nanomedicine. Particular emphasis was placed on ESCRT (Endosomal Sorting Complex Required for Transport) dependent biogenesis mechanisms, molecular cargo profiling, and applications in targeted drug delivery.
Results
Tumor‑derived exosomes play multifaceted roles in cancer progression, including modulation of the tumor microenvironment, facilitation of metastasis, and induction of therapeutic resistance. Their molecular cargo—comprising proteins, lipids, and nucleic acids—serves as a dynamic reflection of the physiological or pathological status of the tumor cells. Technological innovations in exosome isolation, surface modification, and therapeutic payload loading have markedly improved targeted delivery and preclinical treatment outcomes. Notably, drug‑loaded exosomes demonstrate the ability to circumvent multidrug resistance.
Conclusion
Exosomes hold substantial promise for precision oncology through enhanced drug delivery and diagnostic applications. However, clinical translation requires standardized manufacturing, comprehensive safety profiling, and scalable production methods to address current limitations. Emerging strategies such as exosome mimetics and AI‑assisted production optimization poised to address these limitations, guiding the development of personalized, efficient, and targeted cancer treatments.
{"title":"Therapeutic potential of exosomes in malignancies: From drug delivery to clinical application","authors":"Roshni Bibi, Arunika Koley, Koustav Sarkar","doi":"10.1016/j.prp.2026.156381","DOIUrl":"10.1016/j.prp.2026.156381","url":null,"abstract":"<div><h3>Background</h3><div>Cancer remains one of the most pressing global health challenges, with conventional treatments such as chemotherapy and radiotherapy constrained by modest efficacy and severe long‑term adverse effects. Exosomes—nano‑sized extracellular vesicles (30–150 nm) secreted by diverse cell types—have emerged as promising candidates for cancer diagnosis and therapy due to their inherent biocompatibility, low immunogenicity, and ability to cross biological barriers.</div></div><div><h3>Methods</h3><div>A comprehensive review of recent literature was conducted to summarize advancements in exosome biology, isolation techniques, and engineering strategies relevant to cancer nanomedicine. Particular emphasis was placed on ESCRT (Endosomal Sorting Complex Required for Transport) dependent biogenesis mechanisms, molecular cargo profiling, and applications in targeted drug delivery.</div></div><div><h3>Results</h3><div>Tumor‑derived exosomes play multifaceted roles in cancer progression, including modulation of the tumor microenvironment, facilitation of metastasis, and induction of therapeutic resistance. Their molecular cargo—comprising proteins, lipids, and nucleic acids—serves as a dynamic reflection of the physiological or pathological status of the tumor cells. Technological innovations in exosome isolation, surface modification, and therapeutic payload loading have markedly improved targeted delivery and preclinical treatment outcomes. Notably, drug‑loaded exosomes demonstrate the ability to circumvent multidrug resistance.</div></div><div><h3>Conclusion</h3><div>Exosomes hold substantial promise for precision oncology through enhanced drug delivery and diagnostic applications. However, clinical translation requires standardized manufacturing, comprehensive safety profiling, and scalable production methods to address current limitations. Emerging strategies such as exosome mimetics and AI‑assisted production optimization poised to address these limitations, guiding the development of personalized, efficient, and targeted cancer treatments.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156381"},"PeriodicalIF":3.2,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-26DOI: 10.1016/j.prp.2026.156369
Hailah M. Almohaimeed , Hadeel Abdulrahman Waggas , Osama Mohammed Abdulaziz Altowaijri , Jawaher A. Abdulhakim , Zuhair M. Mohammedsaleh , Amany I. Almars , Aniruddha Chatterjee , Bikram Dhara , Daniel Ejim Uti
Exosomes are small vesicles which cells use to communicate with one another by way of transporting proteins, lipids and nucleic acids. They are promising vectors that can be applied in the delivery of drugs and genes to locations because of their natural compatibility with the body, stability, and capability to go through biological barriers. Recent advances in the field of exosome & synthetic biology resulted in new engineering strategies expanding their applicability to therapeutic applications. Scientists can target their surfaces with ligands, antibodies, or peptides to enhance accuracy of targeting, and through the development of more sophisticated loading methods- remote loading, stimuli responsive systems- nucleic acids and small molecules can be delivered effectively. Genetically engineered exosomes can deliver CRISPR/Cas9 available in biological therapy to modify immune responses and invent novel cancer-treatment options. However, high-level production, safety of the immune issues and regulatory approval are still challenges that should be overcome. The review explains the newest approaches and the issues that are yet to be resolved and emphasizes the potential that engineered exosomes can offer as versatile platforms to facilitate precision medicine and treatment of diseases.
{"title":"Exosome precision engineering: A comprehensive method for targeted gene and drug delivery","authors":"Hailah M. Almohaimeed , Hadeel Abdulrahman Waggas , Osama Mohammed Abdulaziz Altowaijri , Jawaher A. Abdulhakim , Zuhair M. Mohammedsaleh , Amany I. Almars , Aniruddha Chatterjee , Bikram Dhara , Daniel Ejim Uti","doi":"10.1016/j.prp.2026.156369","DOIUrl":"10.1016/j.prp.2026.156369","url":null,"abstract":"<div><div>Exosomes are small vesicles which cells use to communicate with one another by way of transporting proteins, lipids and nucleic acids. They are promising vectors that can be applied in the delivery of drugs and genes to locations because of their natural compatibility with the body, stability, and capability to go through biological barriers. Recent advances in the field of exosome & synthetic biology resulted in new engineering strategies expanding their applicability to therapeutic applications. Scientists can target their surfaces with ligands, antibodies, or peptides to enhance accuracy of targeting, and through the development of more sophisticated loading methods- remote loading, stimuli responsive systems- nucleic acids and small molecules can be delivered effectively. Genetically engineered exosomes can deliver CRISPR/Cas9 available in biological therapy to modify immune responses and invent novel cancer-treatment options. However, high-level production, safety of the immune issues and regulatory approval are still challenges that should be overcome. The review explains the newest approaches and the issues that are yet to be resolved and emphasizes the potential that engineered exosomes can offer as versatile platforms to facilitate precision medicine and treatment of diseases.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"280 ","pages":"Article 156369"},"PeriodicalIF":3.2,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.prp.2026.156378
Xuechun Leng , Zhongwu Hu , Mingzhi Zhang , Qiuni Chen , Keping Xu , Jun Zhao
Non-small cell lung cancer (NSCLC) is the most frequent subclass of lung cancer with a gloomy prognosis. Ring finger protein 125 (RNF125), as a ubiquitin E3 ligase, functions on the progression and development of various tumors. This study attempted to address the function and mechanism of RNF125 in NSCLC. The level of RNF125 was predicted with GEPIA2 website and verified in tumor tissues from NSCLC patients. The role of RNF125 in the malignant processes of NSCLC was determined by cell counting kit-8, the 5-ethynyl-2′-deoxyuridine (EdU) incorporation, transwell, flow cytometry and sphere‑formation experiments. The ubiquitinated role of RNF125 on DEAD-box helicase 5 (DDX5) was assessed by co-immunoprecipitation, ubiquitination and cycloheximide assays. The function of RNF125 was revealed in xenografted mice. Low RNF125 expression predicted poor prognosis in NSCLC. RNF125 inhibited the levels of indexes involved in proliferation, migration, invasion and stemness, but promoted apoptosis rate in both A549 and H1299 cells. Mechanically, RNF125 directly bound to DDX5. Overexpression of RNF125 enhanced the DDX5 ubiquitination, but knockdown of RNF125 reduced the degradation of endogenous DDX5. The inhibitory role of RNF125 overexpression in the malignant progressions of A549 cells was recovered with the upregulation of DDX5, vice versa. Besides, overexpression of RNF125 declined tumor weight and volume, the level of Ki-67 and the numbers of liver metastasis foci in vivo, vice versa. Also, RNF125 overexpression reduced the protein expressions of invasion markers and stemness markers in vivo. Collectively, low expression of RNF125 predicted poor prognosis of NSCLC patients. Upregulation of RNF125 repressed proliferation, mobility, invasion and stemness of NSCLC through the ubiquitinated degradation of DDX5.
非小细胞肺癌（NSCLC）是最常见的肺癌亚型，预后不佳。环指蛋白125 （Ring finger protein 125, RNF125）是一种泛素E3连接酶，参与多种肿瘤的发生发展。本研究试图探讨RNF125在非小细胞肺癌中的功能和机制。用GEPIA2网站预测RNF125的水平，并在NSCLC患者的肿瘤组织中进行验证。通过细胞计数试剂盒-8、5-乙基-2′-脱氧尿苷（EdU）掺入、transwell、流式细胞术和成球实验确定RNF125在NSCLC恶性过程中的作用。采用共免疫沉淀法、泛素化法和环己亚胺法评估RNF125对DEAD-box解旋酶5 （DDX5）的泛素化作用。RNF125在异种移植小鼠中的功能被揭示。低RNF125表达预示非小细胞肺癌预后不良。RNF125抑制A549和H1299细胞的增殖、迁移、侵袭和干性等指标水平，但促进细胞凋亡率。机械地，RNF125直接绑定到DDX5。过表达RNF125增强了DDX5的泛素化，而下调RNF125则降低了内源性DDX5的降解。RNF125过表达对A549细胞恶性进展的抑制作用随着DDX5的上调而恢复，反之亦然。RNF125过表达可降低肿瘤重量、体积、Ki-67水平和体内肝转移灶数量，反之亦然。此外，RNF125过表达降低了体内侵袭标志物和干性标志物的蛋白表达。综上所述，RNF125的低表达预示着NSCLC患者的不良预后。RNF125的上调通过DDX5的泛素化降解抑制NSCLC的增殖、移动性、侵袭性和干性。
{"title":"RNF125 suppresses stem cell-like properties and metastasis in non-small cell lung cancer by promoting ubiquitination and degradation of DDX5","authors":"Xuechun Leng , Zhongwu Hu , Mingzhi Zhang , Qiuni Chen , Keping Xu , Jun Zhao","doi":"10.1016/j.prp.2026.156378","DOIUrl":"10.1016/j.prp.2026.156378","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is the most frequent subclass of lung cancer with a gloomy prognosis. Ring finger protein 125 (RNF125), as a ubiquitin E3 ligase, functions on the progression and development of various tumors. This study attempted to address the function and mechanism of RNF125 in NSCLC. The level of RNF125 was predicted with GEPIA2 website and verified in tumor tissues from NSCLC patients. The role of RNF125 in the malignant processes of NSCLC was determined by cell counting kit-8, the 5-ethynyl-2′-deoxyuridine (EdU) incorporation, transwell, flow cytometry and sphere‑formation experiments. The ubiquitinated role of RNF125 on DEAD-box helicase 5 (DDX5) was assessed by co-immunoprecipitation, ubiquitination and cycloheximide assays. The function of RNF125 was revealed in xenografted mice. Low RNF125 expression predicted poor prognosis in NSCLC. RNF125 inhibited the levels of indexes involved in proliferation, migration, invasion and stemness, but promoted apoptosis rate in both A549 and H1299 cells. Mechanically, RNF125 directly bound to DDX5. Overexpression of RNF125 enhanced the DDX5 ubiquitination, but knockdown of RNF125 reduced the degradation of endogenous DDX5. The inhibitory role of RNF125 overexpression in the malignant progressions of A549 cells was recovered with the upregulation of DDX5, <em>vice versa</em>. Besides, overexpression of RNF125 declined tumor weight and volume, the level of Ki-67 and the numbers of liver metastasis foci <em>in vivo</em>, <em>vice versa</em>. Also, RNF125 overexpression reduced the protein expressions of invasion markers and stemness markers <em>in vivo</em>. Collectively, low expression of RNF125 predicted poor prognosis of NSCLC patients. Upregulation of RNF125 repressed proliferation, mobility, invasion and stemness of NSCLC through the ubiquitinated degradation of DDX5.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156378"},"PeriodicalIF":3.2,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1016/j.prp.2026.156374
Chenyan Sui , Zhixuan Zhang , Xin Huang , Likun Han , Changyan Fan , Su Peng , Jun Zhu , Jialong Sun , Jianwei Li , Wang Xiao , Xiaoyan Wang , Xiaodong Zhang , Lingling Hu , Xin Gu
Acute ischemic stroke (AIS), a primary cause of global mortality and disability, involves the sudden interruption of cerebral blood flow, leading to significant neurological impairment. Inflammation plays a critical role in exacerbating brain damage following stroke, making effective anti-inflammatory treatments essential. This study explored the therapeutic potential of anisodine hydrobromide (Ani), a traditional Chinese medicine, in modulating inflammatory responses and glycolysis in the lymphocytes of AIS patients. We evaluated the impact of Ani on peripheral blood mononuclear cells (PBMCs) and purified Treg cells from these patients. Our findings indicated that Ani significantly increased the proportion of Treg cells and upregulated Foxp3 expression, suggesting enhanced anti-inflammatory effects. Ani also reduced the levels of proinflammatory cytokines and inhibited NLRP3 inflammasome activation in T cells. Additionally, Ani influenced glycolysis by downregulating the expression of key glycolytic enzymes, PKM2 and LDHA, through its effects on DNA methylation. Chromatin immunoprecipitation and molecular docking studies revealed that Ani interacts with DNMT1, modifying DNA methylation patterns and increasing 5hmC levels at the promoters of PKM2 and LDHA. These results indicate that Ani exerts neuroprotective effects by modulating both inflammatory and metabolic pathways, suggesting a promising avenue for AIS therapy. Further clinical validation and exploration of the therapeutic efficacy of Ani are warranted to confirm its potential as a treatment for AIS.
{"title":"Anisodine hydrobromide inhibits inflammation and metabolic reprogramming to alleviate the inflammatory response in an acute cerebral infarction model","authors":"Chenyan Sui , Zhixuan Zhang , Xin Huang , Likun Han , Changyan Fan , Su Peng , Jun Zhu , Jialong Sun , Jianwei Li , Wang Xiao , Xiaoyan Wang , Xiaodong Zhang , Lingling Hu , Xin Gu","doi":"10.1016/j.prp.2026.156374","DOIUrl":"10.1016/j.prp.2026.156374","url":null,"abstract":"<div><div>Acute ischemic stroke (AIS), a primary cause of global mortality and disability, involves the sudden interruption of cerebral blood flow, leading to significant neurological impairment. Inflammation plays a critical role in exacerbating brain damage following stroke, making effective anti-inflammatory treatments essential. This study explored the therapeutic potential of anisodine hydrobromide (Ani), a traditional Chinese medicine, in modulating inflammatory responses and glycolysis in the lymphocytes of AIS patients. We evaluated the impact of Ani on peripheral blood mononuclear cells (PBMCs) and purified Treg cells from these patients. Our findings indicated that Ani significantly increased the proportion of Treg cells and upregulated Foxp3 expression, suggesting enhanced anti-inflammatory effects. Ani also reduced the levels of proinflammatory cytokines and inhibited NLRP3 inflammasome activation in T cells. Additionally, Ani influenced glycolysis by downregulating the expression of key glycolytic enzymes, PKM2 and LDHA, through its effects on DNA methylation. Chromatin immunoprecipitation and molecular docking studies revealed that Ani interacts with DNMT1, modifying DNA methylation patterns and increasing 5hmC levels at the promoters of <em>PKM2</em> and <em>LDHA</em>. These results indicate that Ani exerts neuroprotective effects by modulating both inflammatory and metabolic pathways, suggesting a promising avenue for AIS therapy. Further clinical validation and exploration of the therapeutic efficacy of Ani are warranted to confirm its potential as a treatment for AIS.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156374"},"PeriodicalIF":3.2,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146023829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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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