Molecular and Cellular Biochemistry最新文献

{"title":"ROCK2 regulates a stress-responsive transcriptional state and calcium signaling in renal cell carcinoma.","authors":"Zhengdong Hong, Qian Yang, Xiaofang Wei, Cunlong Zhu, Yiqian Wang, Tengfei Hu","doi":"10.1007/s11010-026-05782-w","DOIUrl":"https://doi.org/10.1007/s11010-026-05782-w","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) exhibits marked intratumoral heterogeneity that contributes to disease progression and therapeutic resistance. Although ROCK2 has been implicated in RCC progression, its role in regulating tumor cell heterogeneity and cell-state plasticity remains poorly understood. Using single-cell RNA sequencing, we identified a ROCK2-associated stress-responsive transcriptional state characterized by inflammatory signaling and enhanced calcium pathway activity. ROCK2 knockdown was associated with a lower representation of this transcriptional state together with proliferative tumor cells, and integration with the TCGA-KIRC cohort supported the presence of this stress-associated transcriptional program in bulk RCC tumors. Mechanistically, ROCK2 depletion reduced intracellular calcium levels, suppressed CALM1 and CREB1 expression, promoted apoptosis, and impaired cell-cycle progression and proliferation. Pharmacological restoration of calcium signaling with Bay K8644, together with CALM1 or CREB1 overexpression, partially rescued these defects, supporting functional interactions among ROCK2, calcium signaling, CALM1, and CREB1. Collectively, our findings identify a ROCK2-associated stress-responsive transcriptional state linked to altered calcium signaling and provide new mechanistic insight into RCC cellular heterogeneity, highlighting the functional relationship between ROCK2 and calcium signaling as a potential therapeutic vulnerability in RCC.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207229","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}

{"title":"The METTL3/LOXL2 axis participates in aberrant epithelial-fibroblast crosstalk and induces oral submucous fibrosis in rats.","authors":"Shuhang Fan, Qian Zheng, Zongkang Wang, Ran Xiao, Xuan Zhu, Yanli Liu, Yue Liu, Zhaoyong Hu, Jin Tan","doi":"10.1007/s11010-026-05761-1","DOIUrl":"https://doi.org/10.1007/s11010-026-05761-1","url":null,"abstract":"<p><p>Oral submucous fibrosis (OSF) is an oral potentially malignant disorder strongly associated with the areca nut alkaloids. Although lysyl oxidase-like 2 (LOXL2) is implicated in pathological collagen accumulation and fibrosis, its regulatory role in OSF progression remains unclear. Hematoxylin-eosin, Masson and immunofluorescent staining were performed on rat oral mucosal tissues to assess fibrotic and senescent phenotypes. Senescence of human oral keratinocytes (HOKs) was assessed by senescence-associated β-galactosidase staining, flow cytometry and western blotting. LOXL2 N6-methyladenosine (m6A) methylation levels in tissues and cells were then detected, and methyltransferase-like 3 (METTL3)-LOXL2 interactions were validated using RNA immunoprecipitation and photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation assays. LOXL2 mRNA stability was further assessed after actinomycin D treatment. In addition, lactate levels were measured to explore epithelial-fibroblast crosstalk between HOKs and human oral mucosal fibroblasts. Arecoline-treated rats exhibited progressive epithelial thinning and collagen deposition in oral mucosal tissues, accompanied by upregulated expression of fibronectin, collagen type I, α-smooth muscle actin, p21, and p16. Arecoline exposure elevated reactive oxygen species levels and promoted co-localization of the senescence markers p16/p21 with the epithelial marker cytokeratin. LOXL2 was upregulated in arecoline-induced senescence models, and LOXL2 silencing suppressed fibroblast activation by inhibiting HOKs senescence. Mechanistically, METTL3 stabilized LOXL2 mRNA through m6A-dependent interactions. Downregulation of the METTL3/LOXL2 axis reduced lactate secretion from senescent HOKs, thereby attenuating fibroblast activation. Similar findings were observed in OSF rats. The METTL3/LOXL2 axis may mediate lactate secretion from senescent epithelial cells and regulate epithelial-fibroblast crosstalk during OSF pathogenesis. This study reveals a potential mechanism and candidate targets for further evaluation in OSF.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207280","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}

{"title":"Hyaluronan fragments modulate inflammation in preeclampsia: a focus on Th17/Treg balance.","authors":"Mariana Romao-Veiga, Vanessa Rocha Ribeiro-Vasques, Patrícia Braga da Silva, Gabriela de Oliveira Franco, Larissa Ragozo Cardoso de Oliveira, José Carlos Peraçoli, Maria Terezinha Serrão Peraçoli","doi":"10.1007/s11010-026-05766-w","DOIUrl":"https://doi.org/10.1007/s11010-026-05766-w","url":null,"abstract":"<p><p>Pregnant women with preeclampsia (PE) exhibit an exacerbated inflammatory immune response. Hyaluronan (HA), a damage-associated molecular pattern (DAMP), is increased in the plasma of women with PE and may differentially modulate immune responses depending on its molecular weight. Forty-five women were investigated, including 20 with PE, 20 normotensive (NT) pregnant women, and 5 healthy non-pregnant (NP) women. Plasma samples were obtained for TNF, IL-10, HA, and soluble CD44 (sCD44) analyses by ELISA. Expression of the CD44 receptor, as well as intracytoplasmic transcription factors T-bet (Th1), RORγt (Th17), Foxp3 (Treg), and NF-κB, and intracellular cytokines TNF, IL-17, and IL-10, was assessed by flow cytometry. Experiments were conducted on peripheral blood mononuclear cells, followed by cell culture with or without LMW-HA or high-molecular-weight HA (HMW-HA). Pregnant women with PE showed elevated plasma concentrations of HA and TNF, while sCD44 and IL-10 levels were lower than in the NT group. The percentage of CD44-expressing cells was higher among lymphocytes expressing T-bet, RORγt, TNF, and IL-17. Cell stimulation with LMW-HA increased T-bet and RORγt and decreased FoxP3 expression in NT women. LMW-HA stimulation induced higher NF-κB p65 expression in cells from the NP group. Conversely, cell stimulation with HMW-HA decreased RORγt, IL-17, and TNF expression, while increasing FoxP3 and IL-10 expression in preeclamptic women. Overall, HA molecular weight differentially modulated inflammatory- and regulatory-associated markers, with HMW-HA favoring a more regulatory profile and shifting the inflammatory state toward a regulatory-associated profile.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195324","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}

{"title":"Metabolic links between mitochondrial electron transport, glycolysis, and AMP-activated protein kinase signaling modulate hepatocellular carcinoma cell survival.","authors":"Momoko Uchida, Masato Higurashi, Hidetsugu Nakagawa, Fumihiro Ishikawa, Kazunori Mori, Motoko Shibanuma","doi":"10.1007/s11010-026-05770-0","DOIUrl":"https://doi.org/10.1007/s11010-026-05770-0","url":null,"abstract":"<p><p>Beyond ATP production, mitochondrial metabolism, due to its essential role in cell proliferation and survival, is a potential target for cancer therapy. However, translation into clinical practice is challenging owing to several limitations, including difficulty in distinguishing cancerous and non-cancerous mitochondria, which is further complicated by the heterogeneity of the former. Herein, we focused on cancerous mitochondria exhibiting low DNA/RNA levels and respiratory function compared with those demonstrated by normal cells, and determined the effects of low respiratory activity on the metabolic phenotypes of cancer cells. Interestingly, mitochondria low-type (mt-Low) cells derived from hepatocellular carcinomas were relatively sensitive to electron transport chain (ETC) inhibition. Specifically, cells died under the treatment with the ETC inhibitors, rotenone and antimycin A, at lower doses compared with cells exhibiting normal respiratory activity (mt-psNormal), although ATP levels were sustained in both cell types under these conditions. In mt-psNormal cells, upon ETC inhibition, glycolytic activity increased, and AMP-activated protein kinase was activated, which critically contributed to cell survival. However, these responses were not effectively induced in ETC inhibition-sensitive mt-Low cells. Similar to conventional ETC inhibitors, small interfering RNAs targeting core subunits of respiratory complexes I or III effectively inhibited proliferation (complexes I and III) or survival (complex I) of the tested mt-Low cancer cells, supporting innovative anticancer approaches that target respiratory function using next-generation technology.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195384","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}

{"title":"Octreotide attenuates pancreatic fibrosis through modulation of the HMGB1-Wnt/β-catenin axis in experimental chronic pancreatitis.","authors":"Wenyi Lu, Shungen Huang, Jian Wang, Peng Wan, Bin Wu","doi":"10.1007/s11010-026-05765-x","DOIUrl":"https://doi.org/10.1007/s11010-026-05765-x","url":null,"abstract":"<p><p>Chronic pancreatitis is a progressive fibroinflammatory disease in which activated pancreatic stellate cells and extracellular matrix deposition drive irreversible tissue remodeling. Octreotide has anti-secretory and anti-inflammatory properties, but its anti-fibrotic mechanism remains unclear. To determine whether octreotide attenuates DBTC-induced pancreatic fibrosis through suppression of high-mobility group box 1 (HMGB1) and downstream Wnt/β-catenin signaling. Male Sprague-Dawley rats received dibutyltin dichloride (DBTC, 7 mg/kg) to induce chronic pancreatitis and were assigned to seven groups (n = 10/group) comprising untreated controls, DBTC model rats, and DBTC rats treated with octreotide alone or in combination with HMGB1 overexpression, HMGB1 knockdown, a vector control, or pharmacological Wnt/β-catenin activation. Octreotide was administered at 10 µg/kg/day for 21 days. Pancreatic injury, collagen deposition, stellate cell activation, HMGB1 inflammatory signaling, and Wnt/β-catenin activity were assessed by biochemical assays, histology, hydroxyproline measurement, immunofluorescence, Western blotting, qPCR, and ELISA. DBTC caused weight loss, pancreatic atrophy, elevated amylase/lipase, severe collagen accumulation, and marked increases in collagen I, α-smooth muscle actin (α-SMA), HMGB1, TLR4/RAGE, phospho-NF-κB p65, inflammatory cytokines, active/nuclear β-catenin, Wnt1, phospho-GSK3β, Axin2, c-Myc, and Cyclin D1 (all p < 0.0001 vs. Control). Octreotide substantially reversed these changes, halving fibrosis and hydroxyproline content and suppressing HMGB1 translocation/release (all p < 0.0001 vs. Model). HMGB1 overexpression weakened, whereas HMGB1 knockdown mimicked, octreotide-mediated protection. Wnt activation restored β-catenin activity and fibrosis without significantly changing HMGB1 or TLR4/RAGE/NF-κB signaling (all p > 0.15), a pattern consistent with HMGB1 acting upstream of Wnt/β-catenin. Octreotide limits experimental pancreatic fibrosis by suppressing HMGB1-driven inflammation and downstream Wnt/β-catenin activation, identifying the HMGB1-Wnt/β-catenin axis as a promising anti-fibrotic target.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195329","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}

{"title":"Circadian disruption exacerbates alcohol-induced cardiac injury through impaired cellular quality control and increased cardiomyocyte death.","authors":"Huong Nguyen, Eryn Kirshenbaum, Ruzzell C Flores, Ben Margulets, Victoria Margulets, Erele Tzidon, Drew De Roca, Stefan Balko, Maliha Shaikh, Fabian Preuss, Phillip A Engen, Robin M Voigt, Jeffrey Wigle, Ali Keshavarzian, Lorrie A Kirshenbaum, Inna Rabinovich-Nikitin","doi":"10.1007/s11010-026-05762-0","DOIUrl":"https://doi.org/10.1007/s11010-026-05762-0","url":null,"abstract":"<p><p>Circadian rhythms orchestrate 24-h oscillations in physiology and gene expression in many tissues, including the heart. Disruptions to these rhythms have been linked to increased cardiovascular risk and impaired cellular homeostasis. However, the extent to which circadian disruption influences cardiac responses to environmental stressors such as alcohol, remains poorly understood. Herein, we performed RNA-sequencing and transcriptomic analysis on hearts from C57BL/6 J mice exposed to alcohol for ten weeks and collected at two distinct circadian time points (Zeitgeber Time (ZT)8 and ZT20). Principal component analysis and differential expression profiling revealed robust time-of-day-dependent transcriptional programs induced by alcohol, with significant enrichment of pathways governing mitochondrial quality control, autophagy/mitophagy, ferroptosis, and key signaling nodes (FOXO, MAPK, AMPK, mTOR, HIF, Hippo). To investigate the impact of circadian disruption, we compared alcohol-challenged hearts from circadian disrupted and control mice. Circadian disruption markedly altered transcriptional profiles and pathways associated with cardiomyopathy and insulin resistance, while further amplifying dysregulation of quality control and stress signaling networks. At the cellular level, alcohol exposure reduced autophagosome formation in isolated adult cardiomyocytes and this decrease was exacerbated by circadian disruption. Further, circadian disruption impaired mitochondrial quality control by reducing ATP production, altering mitophagy, and mitochondrial dynamics, resulting in mitochondrial dysfunction. These alterations were accompanied by increased reactive oxygen species (ROS) production and elevated apoptotic cell death compared with either condition alone. Altogether, these findings demonstrate that circadian disruption exacerbates alcohol-induced molecular and cellular cardiac injury by compromising cellular quality control processes, mitochondrial integrity, and cell survival pathways. These findings identify mechanisms that may contribute to increased susceptibility to alcohol-induced cardiac dysfunction and may offer novel approaches to mitigate alcohol-related cardiac injury in shift-workers or individuals with disrupted circadian rhythms.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195367","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}

{"title":"Luteolin inhibits prostate cancer stem cells through disrupting the lactate/H3K18la/β-catenin/LDHA feedback loop.","authors":"Qi Zhang, Xinxiang Ren, Wanshuang Cao, Hongfei Shi, Mingming Zhu","doi":"10.1007/s11010-026-05776-8","DOIUrl":"https://doi.org/10.1007/s11010-026-05776-8","url":null,"abstract":"<p><p>Prostate cancer is one of the most common malignant tumors in men, with prostate cancer stem cells (PCSCs) playing an important role in its initiation and progression. Accumulating evidence has demonstrated that lactate and lactate-mediated histone lactylation are crucial regulators of proliferation, metastasis, immune escape and drug resistance in various cancer. However, their functional roles and underlying mechanisms in PCSCs remain largely elusive. In the present study, we found that lactate levels were significantly elevated in PCSC microenvironment, which effectively induced H3K18 lactylation (H3K18la). The increased-lactate enhanced the stemness of PCSCs. ChIP analysis revealed that H3K18la positively regulated the transcription of the β-catenin gene. Furthermore, β-catenin transcriptionally activated lactate dehydrogenase A (LDHA) to promote lactate production, thereby forming a lactate/H3K18la/β-catenin/LDHA positive feedback loop. Notably, luteolin, a natural flavone, disrupted this feedback loop and exerted potent inhibitory effects on PCSCs. Collectively, our findings uncover a novel lactate-driven regulatory axis in PCSCs and provide new insights into the development of intervention strategies in prostate cancer.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195375","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}

{"title":"Loss of UBE3C-mediated PIM2 ubiquitination drives Helicobacter pylori-induced gastritis via JAK2/STAT3 activation.","authors":"Yan Xiong, Juan Zheng, Yanhuan Tang, Xiaoping Zhu","doi":"10.1007/s11010-026-05774-w","DOIUrl":"https://doi.org/10.1007/s11010-026-05774-w","url":null,"abstract":"<p><p>Helicobacter pylori (H. pylori) infection is a major cause of chronic gastritis, yet its molecular mechanisms remain incompletely understood. In this study, we found that the proviral integration site for Moloney murine leukemia virus kinase 2 (PIM2) was significantly upregulated in H. pylori-infected gastric tissues and cells. Functionally, PIM2 knockdown not only attenuated inflammatory responses both in vivo and in vitro but also significantly reduced gastric H. pylori colonization in mice. Mechanistically, H. pylori infection downregulated the expression of the E3 ubiquitin ligase UBE3C, leading to decreased ubiquitination of PIM2 at K165 and enhanced PIM2 protein stability. Accumulated PIM2 subsequently activated the JAK2/STAT3 pathway, driving inflammatory responses. Combined treatment with the JAK1/2 inhibitor Ruxolitinib further potentiated the anti-inflammatory effects of PIM2 knockdown in H. pylori-infected GES-1 cells and mouse gastric tissues. This study revealed a novel mechanism by which H. pylori promoted gastritis through downregulation of UBE3C, impairment of PIM2 ubiquitination, and activation of the JAK2/STAT3 pathway. The dual benefits of PIM2 knockdown, suppressing inflammation while promoting bacterial clearance, positioned PIM2 as a potential therapeutic target for H. pylori-associated gastritis.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183141","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}

{"title":"SUMO2-mediated SP1 SUMOylation promotes M2 macrophage polarization to facilitate diabetic foot ulcer healing.","authors":"Ziping Yi, Qin Tao, Wenjian Pan, Xia Yao","doi":"10.1007/s11010-026-05754-0","DOIUrl":"https://doi.org/10.1007/s11010-026-05754-0","url":null,"abstract":"<p><p>Diabetic foot ulcers (DFU) present a severe clinical challenge, marked by poor healing, chronic inflammation, and elevated amputation risk. The M2 macrophage is known to support the wound healing of DFU, and syndecan-4 (SDC4) contributes to this process. However, the upstream regulatory mechanisms involving post-translational modifications and transcriptional networks remain unclear. The related molecule levels were measured by RT-qPCR and Western blot. The M2 macrophage biomarkers (IL-10, Arg-1) were detected by ELISA kits, while the number of F4/80⁺CD206⁺ cells was quantified via flow cytometry. The interaction between SP1 and SDC4 was checked by ChIP and dual-luciferase reporter assays. Furthermore, SUMOylation of SP1 was verified through Ni^2⁺ pull-down and Co-IP experiments. CCK-8, Transwell assay, and EdU staining were applied to determine the viability, migration, and proliferation of human dermal fibroblasts (HDF). Furthermore, in the wound tissues of diabetic mice, through HE staining, Masson staining, immunohistochemistry and immunofluorescence detection, the relevant molecular mechanisms in the body were verified. SUMO2, SP1, and SDC4 were upregulated in M2 macrophages. SP1 interacted with the promoter region of SDC4 to transcriptionally activate SDC4. Both SDC4 and SP1 overexpression facilitated HDF proliferation and migration by strengthening the polarization of M2 macrophages. However, subsequent knockdown of SDC4 could reverse the promoting effects induced by SP1 overexpression. SUMO2 mediated the SUMOylation of SP1 at the K16 site and increased its protein stability. The inhibition of SP1 SUMOylation impeded M2 phenotype polarization, thereby decreasing HDF viability and suppressing their proliferative and migratory capability under high-glucose conditions. In vivo, topical application of ginkgolic acid (GA) to diabetic mouse wounds significantly decreased the wound healing rate. SUMO2 stabilizes SP1 protein by mediating its SUMOylation at K16, and SP1 subsequently activates SDC4 transcription to facilitate M2 macrophage polarization, thereby promoting wound healing in a diabetic mouse wound model.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183276","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}

{"title":"Morin counteracts KBrO₃-induced hepatotoxicity by reprogramming the HOTAIR/MEG3-miR-125b-5p/miR-214-5p axis and suppressing STAT1-associated RIPK3/MLKL necroptotic signaling.","authors":"Muhammed Raşit Özer, Selçuk Özdemir, Sefa Küçükler, Mustafa Özkaraca, Hamit Emre Kızıl, Nurhan Akaras, Hüseyin Mutlu, Fatih Mehmet Kandemir","doi":"10.1007/s11010-026-05775-9","DOIUrl":"https://doi.org/10.1007/s11010-026-05775-9","url":null,"abstract":"<p><p>Potassium bromate (KBrO₃; PB), an oxidative contaminant in ozonated water and bakery products, induces multi-mechanistic hepatotoxicity. Its epigenetic, necroptotic, and metabolic injury dimensions remain poorly characterized. Morin (MOR), a dietary flavonoid with established antioxidant and anti-inflammatory properties, has not previously been evaluated against PB-induced subacute hepatotoxicity. To characterize MOR's hepatoprotective mechanisms against PB-induced liver injury, focusing on the HOTAIR/MEG3-miRNA epigenetic axis, STAT1-associated RIPK3/MLKL necroptotic signaling, and Glut2/HPGD-AKT/mTOR metabolic signaling. Male Sprague-Dawley rats (n = 28) were assigned to Control, MOR (100 mg/kg), PB (62 mg/kg), and PB + MOR groups for 14 days. Outcomes included hepatobiliary biochemistry, oxidative stress markers, inflammatory mediators (ELISA), lncRNA/miRNA/mRNA profiling (RT-qPCR), immunohistochemistry (RIPK3, MLKL), double immunofluorescence (Glut2/AKT1; HPGD/mTOR), histopathology, and PCA. PB produced marked redox imbalance (↑MDA; ↓SOD, CAT, GPx), NF-κB/NLRP3-associated inflammatory mediator elevation, epigenetic disruption (↑HOTAIR, ↓MEG3; ↑miR-125b-5p/↓BCL2L2; ↓miR-214-5p/↑SMAD4), upregulation of STAT1-associated necroptosis-related transcripts and proteins (↑RIPK1/RIPK3/MLKL), and metabolic dysfunction (↓Glut2, ↓HPGD; ↑AKT1/mTOR). MOR restored redox balance, suppressed inflammation, and reprogrammed the miRNA axis while normalizing MLKL (transcript and immunohistochemistry) and AKT1 and partially attenuating RIPK3, mTOR, and STAT1. MOR confers multi-targeted hepatoprotection by restoring redox and metabolic homeostasis, attenuating NF-κB/NLRP3-associated inflammation, reprogramming HOTAIR/MEG3-miRNA epigenetics, and attenuating STAT1-associated RIPK3/MLKL signaling, supporting its potential as a dietary hepatoprotective candidate. PB is associated with engagement of the hepatic STAT1/RIPK3/MLKL axis and disrupts the HOTAIR/MEG3-miRNA network-both previously undocumented for this toxicant. MOR partially restores miR-214-5p/miR-466 expression while suppressing their downstream effector SMAD4, consistent with attenuation of pro-fibrotic signaling. Future work should employ multi-dose designs, in vitro mechanistic dissection, sex-stratified analyses, and clinical pharmacokinetic profiling to advance MOR toward translational application.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183285","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}