Pharmacological research最新文献

{"title":"Should mitochondrial membrane potential be reconsidered as a criterion of cell death?","authors":"Petr Mlejnek","doi":"10.1016/j.phrs.2026.109696","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109696","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109696"},"PeriodicalIF":12.2,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nifedipine-modulated gut microbiota attenuates hypertensive vascular injury through Bifidobacterium-associated inosine-Adora2b signaling.","authors":"Xiaoyu Ren, Xuefang Yan, Ping Tang, Jiajia Jin, Zihan Qin, Yun Zhang, Tongxue Zhang, Guixiang Yao, Xianlun Yin, Zhuo Zhao, Zhe Wang, Qunye Zhang","doi":"10.1016/j.phrs.2026.109684","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109684","url":null,"abstract":"<p><p>Although antihypertensive drugs mitigate hypertensive vascular injury, their vascular benefits are not fully explained by blood pressure reduction alone. Many cardiovascular drugs reshape the gut microbiota, which in turn influences their vascular pharmacology. We therefore investigated whether gut microbiota remodeling contributes to nifedipine-mediated vascular protection in high-salt hypertensive rats and a pilot patient cohort. Combining 16S rRNA sequencing, untargeted metabolomics, fecal microbiota transplantation, microbiota depletion, supplementation, and selective receptor antagonism, we found that nifedipine ameliorated gut dysbiosis. Transplantation of nifedipine-modulated microbiota improved intestinal barrier integrity and reduced vascular inflammation, oxidative stress, collagen deposition, and vascular smooth muscle cell (VSMC) phenotypic switching, while only marginally lowering blood pressure. Conversely, microbiota depletion markedly attenuated these vascular benefits despite preserving nifedipine-induced blood pressure lowering. These vascular benefits were associated with nifedipine-restored Bifidobacterium animalis subsp. lactis 420 (B420) and increased inosine availability. Supplementation with either recapitulated major vascular protective effects of nifedipine without statistically significant changes in blood pressure. In hypertensive patients, nifedipine treatment was associated with higher intestinal B420 abundance and inosine levels. In vitro, inosine modulated macrophages in an Adora2b- and Rap1-dependent manner, with accompanying changes in cAMP and KLF4, ameliorating VSMC dysfunction via paracrine signaling. In vivo, systemic Adora2b antagonism attenuated the vascular protective effects of both inosine and B420. Together, our findings support a gut microbiota-dependent component of nifedipine-mediated vascular protection that extends beyond blood pressure lowering, involving B420, increased inosine availability, and Adora2b signaling. We also nominate B420 and inosine as candidate adjuncts to calcium channel blocker therapy.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109684"},"PeriodicalIF":12.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-ketoglutarate ameliorates systemic sclerosis-associated fibrosis by restoring endothelial function.","authors":"Yanting Wu, Shikai Ye, Huanling Chen, Jiahui Li, Xiang Pan, Huajuan Yan, Haiyan Chu, Qingmei Liu, Xiangzhen Kong, Jun Bian, Zhenglong Gu, Weilin Pu","doi":"10.1016/j.phrs.2026.109686","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109686","url":null,"abstract":"<p><p>Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by multi-organ fibrosis with limited therapeutic options. Using targeted metabolomics, we first observed that levels of alpha-ketoglutarate (α-KG), a key TCA-cycle intermediate, were paradoxically elevated in bleomycin-induced fibrotic lungs and in TGF-β-stimulated fibroblasts, prompting us to test whether exogenous supplementation could augment this compensatory response. Using bleomycin-induced skin and lung fibrosis mouse models, we demonstrated that oral α-KG administration significantly attenuated dermal and pulmonary collagen deposition, reduced inflammatory infiltration, and improved survival. Although fibroblasts are conventionally regarded as the central effectors of fibrosis, integrated single-cell RNA sequencing and bulk transcriptomic deconvolution unexpectedly identified endothelial cells as the predominant cellular target of α-KG in fibrotic lungs. Consistently, α-KG restored endothelial cell proportions in vivo, rescued angiogenic function and preserved barrier integrity in association with upregulation of eNOS, and tight junction proteins in human umbilical vein endothelial cells (HUVECs) treated with bleomycin. Mechanistically, α-KG suppressed TGF-β/Smad activation and reversed bleomycin-induced metabolic repression, including restoration of fatty acid oxidation signatures and mitochondrial ultrastructure, accompanied by upregulation of the mitochondrial biogenesis regulator NRF1. Collectively, these findings reveal that α-KG exerts broad anti-fibrotic effects in SSc models by protecting endothelial function and inhibiting canonical pro-fibrotic signaling, highlighting its potential as a translatable metabolic therapeutic strategy for SSc.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109686"},"PeriodicalIF":12.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated Metal Homeostasis in Alzheimer's Disease: From Pathological Modulators to Therapeutic Targets.","authors":"Jiaoyan Yang, Fan Lou, Wei Sun, Ming Li, Lai Su, Yaqian Wang, Pingan Li, Jingyang Su","doi":"10.1016/j.phrs.2026.109690","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109690","url":null,"abstract":"<p><p>The \"metal ion hypothesis\" of Alzheimer's disease (AD) has gained widespread acceptance, but translating this understanding into effective therapies remains elusive. This likely stems from a simplistic understanding of metal homeostasis as merely a matter of \"excess and deficiency.\" This article reviews the context-dependent roles of iron, copper, zinc, aluminum, and manganese in the pathogenesis of AD, with a particular focus on their bidirectional interactions with classic AD pathology (the ferroptosis hypothesis is relatively mature, while emerging hypotheses such as cuproptosis have not been fully elucidated). Metal homeostasis dysregulation can directly promote β-amyloid aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and regulated cell death. Conversely, these pathological processes can also alter the binding, storage, transport, and subcellular distribution of metal ions. Dysregulated metal ions function as \"context-dependent\" modulators of pathological processes. Their functional effects depend on metal species, concentration, binding state, subcellular compartment, and disease stage. Metal homeostasis dysregulation associated with AD may essentially reflect a redistribution between physiological and pathological pools. Ideal interventions should selectively neutralize pathological metal pools while preserving or restoring essential metal-dependent neuronal functions. By integrating the latest advances in the field of metal-targeted therapies (chelators, metabolic modulators, biomarkers, metal imaging, and gene editing), we emphasize that future treatments should shift from nonspecific metal clearance toward precise metal regulation and precision medicine.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109690"},"PeriodicalIF":12.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-dose juglone attenuates pressure overload-induced cardiac hypertrophy through Lys207-dependent FoxO1 activation and mitochondrial protection.","authors":"Hongyu Chen, Zhihao Yang, Cheng Zhang, Chengxin Ge, Yingliang Zhao, Shaopeng Cheng, Yilin Wang, Hao Chen, Can Xu, Dongjin Wang, Jie Yang","doi":"10.1016/j.phrs.2026.109685","DOIUrl":"10.1016/j.phrs.2026.109685","url":null,"abstract":"<p><p>Pressure overload-induced cardiac hypertrophy is characterized by mitochondrial dysfunction and redox imbalance. Here, we investigated the efficacy, safety window, and redox-regulatory mechanism of juglone, a naturally occurring 5-hydroxy-1,4-naphthoquinone. In mice subjected to transverse aortic constriction (TAC), high-dose juglone induced cardiac, hepatic, and renal toxicity, whereas 1 mg/kg/day was well tolerated and attenuated cardiac hypertrophy. Juglone also suppressed Ang II-induced cardiomyocyte hypertrophy in vitro and preserved mitochondrial ultrastructure and mitochondrial membrane potential, respiration, ATP production, and redox homeostasis. Single-nucleus RNA sequencing (snRNA-seq) revealed that juglone reduced stress-associated cardiomyocyte states and enriched calcium-handling cardiomyocytes. Integrated transcriptomic analyses, Biotin-Juglone pull-down assay, surface plasmon resonance, cellular thermal shift assays, molecular docking, and mutational analyses identified FoxO1 as a functional target of juglone. Juglone engaged the FoxO1 DNA-binding domain in a Lys207-dependent manner, and was associated with FoxO1 deacetylation, nuclear accumulation, and transcriptional activation. Activated FoxO1 induced Sesn3 transcription and restored AMPK phosphorylation at Thr172. Sesn3 silencing markedly attenuated juglone-induced AMPK activation and impaired its protective effects against cardiomyocyte hypertrophy and mitochondrial dysfunction. FoxO1 silencing, FoxO1-K207Q mutation, blockade of FoxO1 deacetylation, or inhibition of FoxO1 transcriptional activity impaired these benefits. Importantly, myocardium from patients with aortic valve stenosis-associated hypertrophy exhibited increased FoxO1 acetylation, reduced cardiomyocyte nuclear FoxO1 localization, decreased Sesn3 expression and AMPK phosphorylation, and increased 4-HNE. Collectively, low-dose juglone attenuates pathological hypertrophy and preserves mitochondrial homeostasis through the FoxO1-Sesn3-AMPK axis, while highlighting the importance of dose-dependent redox effects in determining its therapeutic efficacy and systemic toxicity.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109685"},"PeriodicalIF":12.2,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SERINC3 promotes oral squamous cell carcinoma progression and mitochondrial metabolic reprogramming involving c-MET/JNK/PGC-1α axis.","authors":"Shuiqing Yu, Qiong Zhang, Haoyu Cheng, Shaofen Xu, Zhihe Fu, Zhichao Zheng, Jiannan Zhou, Wei Xie, Qianqian He, Haohui Zhu, Jiang Li, Janak Lal Pathak, Liang Qiao, Lihong Wu","doi":"10.1016/j.phrs.2026.109681","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109681","url":null,"abstract":"<p><p>Serine incorporator 3 (SERINC3) is a multi-transmembrane protein involved in membrane lipid biosynthesis but its role in oral squamous cell carcinoma (OSCC) is undefined. Combining clinical specimens with public transcriptomic datasets, we found that SERINC3 was upregulated in OSCC tissues and that high expression was associated with poorer overall survival. Functionally, SERINC3 depletion impaired OSCC cell proliferation, migration, and invasion, whereas SERINC3 overexpression enhanced these phenotypes. In vivo, Serinc3 deletion suppressed 4NQO-induced oral tumorigenesis, and SERINC3 knockdown reduced tumor growth in both subcutaneous and patient-derived xenograft models. Mechanistically, SERINC3 sustained c-MET expression, and knockdown of either SERINC3 or MET increased JNK phosphorylation and PGC-1α levels; JNK inhibition with JNK-IN-8 partially reversed the phenotypic effects of SERINC3 depletion, while pharmacological PGC-1α activation with ZLN005 suppressed migration and invasion in vitro and xenograft growth in vivo. Single-cell RNA sequencing and metabolic assays further linked SERINC3 to mitochondrial metabolic reprogramming. Together, these findings identify SERINC3 as a candidate driver of OSCC progression acting through c-MET/JNK/PGC-1α-associated signaling and mitochondrial metabolic regulation, and suggest it as a potential therapeutic target. The precise causal relationships within this signaling axis warrant further investigation.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109681"},"PeriodicalIF":12.2,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the role of histone deacetylases and histone deacetylase inhibitors in obesity and emerging evidence from Anorexia Nervosa.","authors":"Emanuela Micioni Di Bonaventura, Luca Botticelli, Mariangela Pucci, Giacomo Einaudi, Elena Conte, Maurizio Crestani, Annamaria De Luca, Francesco Alessandro Palermo, Carlo Cifani, Maria Vittoria Micioni Di Bonaventura","doi":"10.1016/j.phrs.2026.109694","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109694","url":null,"abstract":"<p><p>Histone deacetylases (HDACs) are key epigenetic regulators that modulate chromatin accessibility and transcriptional programs controlling metabolism, energy balance, and reward-related behaviors. Aberrant HDACs activity contributes to metabolic dysfunction by altering adipogenesis, thermogenic capacity, lipid profile, and hypothalamic circuits governing appetite. In obesity, specific HDAC isoforms promote adipocyte hypertrophy, impair browning of white adipose tissue, disrupt mitochondrial function, and exacerbate inflammation and insulin resistance. HDAC inhibitors (HDACi) counteract these effects by enhancing oxidative metabolism, stimulating thermogenesis, reducing adipocyte size, and improving systemic glucose and lipid homeostasis in preclinical models. Beyond peripheral metabolism, HDACi can also modulate neural pathways implicated in food intake, highlighting their potential influence in eating disorders, an area of research currently largely limited to anorexia nervosa. Research on HDACs, HDACi, and eating disorders is relatively recent; therefore, the characterization of potential molecular alterations and the identification of specific HDAC targets remain areas of ongoing development. Collectively, current evidence suggests that selective targeting of HDACs may offer a promising therapeutic strategy to correct epigenetic dysfunctions underlying both obesity and maladaptive feeding behaviors; however, translating these findings into clinical practice will require overcoming key challenges, including achieving isoform-specific selectivity, minimizing central nervous system-related side effects, and establishing efficacy and safety in human studies.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109694"},"PeriodicalIF":12.2,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FGF21-NR1D1 Signaling Restrains the CYP4A/20-HETE/GPR75 Axis to Counteract Integrated Renal-Vascular Injury in Hypertension.","authors":"Wang Guiyun, Qiu Feng, Li Supeng, Xu Guangsen, Feng Qiyang, Xue Yongguo, Wang Shenyu, Liu Shibo, Jin Jiajia, Han Bingyan, Wang Suntao, Pan Jingye, Wang Baile, Wang Cong, Pan Xuebo","doi":"10.1016/j.phrs.2026.109683","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109683","url":null,"abstract":"<p><p>Hypertension leads to concomitant injuries in the kidney and vasculature, yet the molecular mechanisms underlying this coordinated pathology remain incompletely understood. Here, we identify activation of the CYP4A/20-HETE/GPR75 axis as being associated with coordinated renal and vascular injury in hypertension. In hypertension, this pathway was concurrently activated in the liver, kidney, and vasculature and was associated with renal fibrosis, endothelial dysfunction, and oxidative stress. Pharmacological inhibition of CYP4A attenuated these pathological changes, supporting a functional contribution of this axis to hypertensive organ injury. Genetic and pharmacological evidence further demonstrated that FGF21 acts as an endogenous negative regulator of CYP4A/20-HETE signaling. Mechanistically, FGF21 restored expression of the nuclear receptor NR1D1, which was suppressed under hypertensive conditions, and this effect was associated with reduced CYP4A expression independently of ERK1/2 signaling. The functional relevance of the FGF21-NR1D1 axis was supported by the observation that NR1D1 antagonism largely abolished the protective effects of FGF21. Thus, these findings elucidate a mechanistic axis linking FGF21-NR1D1 signaling to the CYP4A/20-HETE/GPR75 pathway and suggest that modulation of this pathway may represent a potential therapeutic strategy for hypertensive renal and vascular injury.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109683"},"PeriodicalIF":12.2,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149194751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lentinan-induced FUBP1 O-GlcNAcylation suppresses macrophage ferroptosis and atherosclerosis via the Tp53/SLC7A11 axis.","authors":"Xiaohui Liu, Ziqin Xu, Feiyang Cheng, Shuiqing Hu, Miaomiao He, Wei Zheng, Haoran Wei, Jie Li, Han Yang, Lu Fang, Yan Wang, Lemin Zheng, Xiaoquan Rao, Qin Fang","doi":"10.1016/j.phrs.2026.109676","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109676","url":null,"abstract":"<p><p>Atherosclerosis remains a leading cause of cardiovascular mortality, driven by macrophage dysfunction and necrotic core expansion. Ferroptosis, an iron-dependent cell death, is a critical driver of plaque instability; however, pharmacological interventions targeting ferroptosis remain scarce. Lentinan (LNT), a bioactive β-(1,3)-glucan extracted from shiitake mushrooms, exhibits potent antioxidant properties but its potential role in the modulation of macrophage ferroptosis remains unexplored. We investigated the therapeutic potential and molecular mechanisms of action of LNT in atherosclerosis. LNT administration significantly attenuated atherosclerotic progression in mice. Specifically, LNT mitigated macrophage ferroptosis by enhancing glutathione homeostasis and reducing lipid peroxidation. Notably, these protective effects were significantly abrogated in mice deficient in solute carrier family 7 member 11 (SLC7A11), indicating that the effect of LNT is dependent on this molecule. We found that LNT directly binds to far upstream binding protein 1 (FUBP1) and that T559 is required for FUBP1 O-GlcNAcylation and subsequent nuclear translocation. In the nucleus, FUBP1 binds to tumor protein p53 (Tp53), thereby relieving the transcriptional repression of SLC7A11. The resulting activation of the SLC7A11 signaling axis not only inhibits ferroptosis but also promotes scavenger receptor B type 1 (SR-B1)-mediated cholesterol efflux. These findings highlight LNT as a novel modulator of the FUBP1/Tp53/SLC7A11 axis, offering a promising natural therapeutic strategy to stabilize atherosclerotic plaques.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109676"},"PeriodicalIF":12.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay Between Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Inflammatory Bowel Disease: From Molecular Mechanisms to Therapeutic Opportunities.","authors":"Shuangshuang Li, Tongyou Zou, Jiaxuan Tian, Yanjun Li, Yinglong He, Shunhua Zhou, Haibin Wu, Meiyan Zeng, Houpan Song","doi":"10.1016/j.phrs.2026.109687","DOIUrl":"https://doi.org/10.1016/j.phrs.2026.109687","url":null,"abstract":"<p><p>Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are key pathogenic drivers in inflammatory bowel disease (IBD). Chronic ER stress impairs epithelial barrier integrity and stimulates inflammatory pathways, causing cell death. Simultaneously, mitochondrial dysfunction results in excessive reactive oxygen species production, bioenergetic failure, and defective mitophagy, further disrupting intestinal homeostasis. Notably, these two organellar stress responses are physically and functionally linked via mitochondria-ER contacts (MERCs), which form signaling platforms-mitochondria-associated ER membranes. These platforms coordinate calcium transfer and redox signaling while integrating autophagy and the unfolded protein response (UPR). This review comprehensively summarizes the current molecular mechanisms by which ER stress and mitochondrial dysfunction aid IBD pathogenesis, emphasizing calcium homeostasis imbalance, oxidative stress, disrupted mitochondrial quality control, and autophagy-UPR integration. Furthermore, this article highlights the functional interplay between the ER and mitochondria, as well as the MERCs that structurally connect them. Additionally, it discusses emerging diagnostic biomarkers and therapeutic strategies based on these mechanisms, aiming to offer theoretical insights and novel perspectives for IBD research and clinical intervention.</p>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":" ","pages":"109687"},"PeriodicalIF":12.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}