Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"The role of Nir2, a lipid-transfer protein, in regulating endothelial cell functions","authors":"Zydrune Polianskyte-Prause ,&nbsp;Amita Arora ,&nbsp;Juuso H. Taskinen ,&nbsp;Vaishali Chaurasiya ,&nbsp;Salla Keskitalo ,&nbsp;Antti Tuhkala ,&nbsp;Ida Hilska ,&nbsp;Markku Varjosalo ,&nbsp;Vesa M. Olkkonen","doi":"10.1016/j.bbamcr.2025.119926","DOIUrl":"10.1016/j.bbamcr.2025.119926","url":null,"abstract":"<div><div>Lipid transfer proteins regulate the metabolism of phosphoinositides with key roles in cell signaling, membrane and actin dynamics, intracellular trafficking, and diseases. Nir2/PITPNM1 acts as a cellular phosphatidylinositol/phosphatidic acid (PI/PA) exchanger that maintains phosphoinositide signaling at the plasma membrane (PM) and endoplasmic reticulum (ER) membrane contact sites. Here, we assessed the function of Nir2 in human umbilical vein endothelial cells (HUVECs), by analyzing the impacts of Nir2 knockdown (KD) on angiogenesis in vitro, cell viability, proliferation, migration, actin cytoskeletal regulation and vascular endothelial growth factor (VEGF)-mediated downstream cellular signaling pathways. We show that Nir2 KD inhibits angiogenic tube formation in HUVECs, reduces cell viability, proliferation and migration, as well as diminishes actin stress fibers, while Nir2 overexpression increases cell viability and overexpression of an shRNA-resistant Nir2 construct rescues it. Nir2 KD results in decreased activity of AKT and ERK signaling pathways upon VEGF stimulus, plausibly underlying the observed defects in proliferation, migration and angiogenesis. In addition, our interactome analysis confirmed an interaction of Nir2 with the membrane contact site organizer VAPA (vesicle-associated membrane protein-associated protein A), validated by co-immunoprecipitation and co-localization analyses. VAPA KD inhibited angiogenesis similar to that of Nir2, and double KD of the two tended to have even stronger inhibitory effect. A number of other tentative partners of Nir2 were detected; according to STRING analysis, these likely represent indirect interactions driven by a complex with VAPA. The present findings unravel new avenues to understanding the molecular mechanisms by which Nir2 regulates key endothelial functions such as angiogenesis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119926"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143508676","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":"Lactylation and regulated cell death","authors":"Wenlong Zhang ,&nbsp;Guangyao Shan ,&nbsp;Guoshu Bi,&nbsp;Zhengyang Hu,&nbsp;Yanjun Yi,&nbsp;Dejun Zeng,&nbsp;Zongwu Lin,&nbsp;Cheng Zhan","doi":"10.1016/j.bbamcr.2025.119927","DOIUrl":"10.1016/j.bbamcr.2025.119927","url":null,"abstract":"<div><div>Lactylation, a newly identified post-translational modification, entails the attachment of lactate to lysine residues within proteins, profoundly modulating diverse cellular mechanisms underlying regulated cell death (RCD). This modification encompasses two primary categories: histone lactylation and non-histone lactylation. Histone lactylation assumes a pivotal regulatory function in the RCD process, primarily by modulating the transcriptional landscape of genes implicated in cell death. In contrast, non-histone lactylation exerts its influence by targeting transferases, transcription, cell cycle progression, death pathways, and metabolic processes that are intricately involved in RCD. This review provides a comprehensive overview of recent breakthroughs in understanding how lactylation regulates RCD, while also offering insights into potential avenues for future research, thereby deepening our comprehension of cellular fate determination.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 4","pages":"Article 119927"},"PeriodicalIF":4.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529611","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":"Totipotent-like reprogramming: Molecular machineries and chemical manipulations","authors":"Wanting Cai ,&nbsp;Lingci Huang ,&nbsp;Xinwei Wu,&nbsp;Haotian Zhang,&nbsp;Zhuoning Fang,&nbsp;Xiao-Min Liu","doi":"10.1016/j.bbamcr.2025.119925","DOIUrl":"10.1016/j.bbamcr.2025.119925","url":null,"abstract":"<div><div>Embryonic stem cells (ESCs) exhibit remarkable pluripotency, possessing the dual abilities of self-renewal and differentiation into any cell type within the embryonic lineage. Among cultivated mouse ESCs, a subpopulation known as 2-cell-like cells (2CLCs) displays a transcriptomic signature reminiscent of the 2-cell embryonic stage, with the capacity to differentiate into both embryonic and extraembryonic tissues. These 2CLCs have served as an invaluable totipotent-like cell model for deciphering the cellular and molecular mechanisms underlying the establishment of totipotency. Accumulating evidence has indicated that a multitude of regulators including transcription factors, epigenetic modifications, and RNA regulators, exert crucial functions in the reprogramming of ESCs towards 2CLCs. In addition to 2CLCs, alternative totipotent-like cell types can be induced and maintained through the administration of single or combined chemical supplements, offering promising cell resources for regenerative medicine. In this review, we summarize the current advancements in the molecular regulations of 2CLCs and chemical manipulations of totipotent-like cells in mice, providing a foundation for understanding the regulatory networks underlying cell totipotency.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119925"},"PeriodicalIF":4.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488436","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":"Aberrant miRNA expression and protein arginine methyltransferase 5 (PRMT5) in cancer: A review","authors":"Saïd Sif,&nbsp;Majdi Al Alawneh","doi":"10.1016/j.bbamcr.2025.119923","DOIUrl":"10.1016/j.bbamcr.2025.119923","url":null,"abstract":"<div><div>The search for important factors involved in triggering and promoting cancer cell growth and survival has led to the identification of key players, including transcription factors, chromatin remodelers, epigenetic modifying enzymes, signaling molecules, and miRNAs. However, the interplay and crosstalk between some of these factors and the impact they have on tumorigenesis remains largely unexplored. In this review, we focus on type II protein arginine methyltransferase 5 (PRMT5)-mediated epigenetic silencing and its regulatory tumor suppressor miRNAs, as well as the mechanisms by which circular PRMT5 RNA (circ-PRMT5) promotes cancer cell proliferation and survival.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119923"},"PeriodicalIF":4.6,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senolytic elimination of senescent cells improved periodontal ligament stem cell-based bone regeneration partially through inhibiting YAP","authors":"Linglu Jia ,&nbsp;Han Xiao ,&nbsp;Zhenghao Hao ,&nbsp;Shaoqing Sun ,&nbsp;Wenxi Zhao ,&nbsp;Zikai Gong ,&nbsp;Weiting Gu ,&nbsp;Yong Wen","doi":"10.1016/j.bbamcr.2025.119921","DOIUrl":"10.1016/j.bbamcr.2025.119921","url":null,"abstract":"<div><div>Periodontal ligament stem cell (PDLSC)-based tissue engineering is an important method to promote periodontal tissue regeneration. However, PDLSCs are susceptible to the effects of replicative senescence, leading to reduced proliferation and differentiation abilities and weakened tissue regeneration potential. Senolytics (the combination of dasatinib and quercetin) are drugs that inhibit cellular aging through inducing the apoptosis of senescent cells, but whether they have positive effects during the senescence of PDLSCs is unknown. The present study established a long-term in vitro culture model of PDLSCs and then analyzed the effects of senolytics on the senescence, apoptosis, and osteogenic differentiation of PDLSCs in vitro and PDLSC-based tissue regeneration in vivo. The results showed that senolytics delayed the process of aging in prolonged-cultured PDLSCs and promoted the elimination and apoptosis of senescent cells. Moreover, senolytics improved the osteogenic differentiation ability of both young and senescent PDLSCs in vitro and promoted PDLSC-based alveolar bone regeneration in vivo. Furthermore, senolytics inhibited the expression of YAP in senescent PDLSCs. Their antiaging effects were enhanced when combined with the YAP inhibitor verteporfin, but were inhibited when combined with the YAP activator NIBR-LTSi. Taken together, these findings suggest that senolytics promoted the elimination of senescent PDLSCs and enhanced senescent PDLSC-based bone regeneration, partially through the inhibition of YAP expression.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119921"},"PeriodicalIF":4.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438282","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":"NUAKs facilitate mTOR-mediated NSCLC proliferation and metastasis by modulating glucose metabolism and inhibiting p53 activity","authors":"Jaithanya Yesupogu Moorthy Babu,&nbsp;Ravi Manoharan","doi":"10.1016/j.bbamcr.2025.119922","DOIUrl":"10.1016/j.bbamcr.2025.119922","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) cells frequently exhibit aberrant glucose metabolism, characterized by elevated aerobic glycolysis, pentose phosphate pathway (PPP), and reduced oxidative phosphorylation. However, the specific mechanisms underlying the abnormal activation of glucose metabolism and its contribution to NSCLC tumorigenesis remain incompletely elucidated. In this study, we observed that both NUAK1 and NUAK2 mRNA expression levels were significantly elevated in NSCLC tissues compared to non-tumor tissues, and that high NUAK1/2 expression correlated with poor prognosis in NSCLC patients. Furthermore, NUAK1/2 promotes aerobic glycolysis and PPP in NSCLC cells and stimulates cellular proliferation and migration. Depletion or inhibition of NUAK1/2 results in decreased aerobic glycolysis, PPP activity, cell proliferation, and migration, leading to increased apoptosis of NSCLC cells. Mechanistically, NUAK1/2 enhances mTOR activity by suppressing the activity of p53, thereby promoting NSCLC cell growth and metastasis through the promotion of aerobic glycolysis and PPP. Our findings suggest that NUAK1/2 plays a crucial role in glucose reprogramming and tumorigenesis in NSCLC cells, indicating that targeting NUAK1/2 may represent a potential therapeutic strategy for NSCLC metabolism.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119922"},"PeriodicalIF":4.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429659","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":"Novel therapeutic insights into pathological cardiac hypertrophy: tRF-16-R29P4PE regulates PACE4 and metabolic pathways","authors":"Feng Wang ,&nbsp;Ping Li ,&nbsp;Xinxin Yan ,&nbsp;Anna Yue ,&nbsp;Jingyi Xu ,&nbsp;Yaqing Shao ,&nbsp;Kaiyu Zhang ,&nbsp;Qian Zhang ,&nbsp;Yuan Li ,&nbsp;Kangyun Sun","doi":"10.1016/j.bbamcr.2025.119920","DOIUrl":"10.1016/j.bbamcr.2025.119920","url":null,"abstract":"<div><div>Pathological cardiac hypertrophy (PCH) is a complex condition with an incompletely understood pathogenesis. Emerging evidence suggests that transfer RNA-derived small RNAs (tsRNAs) may play a significant role in various cellular processes, yet their impact on PCH remains unexplored. In this study, we performed tsRNA sequencing on plasma samples from PCH patients and identified a marked decrease in the expression of tRNA-related fragment 16-R29P4PE (tRF-16-R29P4PE), a specific tsRNA fragment, with a diagnostic area under the curve value of 0.7750. Using Angiotensin II (Ang II)-stimulated H9c2 cardiomyocytes as an <em>in vitro</em> model and Sprague-Dawley rats as an <em>in vivo</em> model, we investigated the effects of tRF-16-R29P4PE minic/inhibitors and silencing of the paired basic amino acid cleaving system 4 (PACE4) gene. Our results demonstrated that modulating tRF-16-R29P4PE expression significantly reduced brain natriuretic peptide (BNP) and free fatty acid levels while enhancing ATP production, glucose levels, and mitochondrial membrane potential. These effects were accompanied by the downregulation of PACE4, hypoxia-inducible factor-1α (HIF-1α), glucose transporter-4 (GLUT-4), and medium-chain acyl-CoA dehydrogenase (MCAD), as well as the upregulation of peroxisome proliferator-activated receptor α (PPARα). Animal experiments revealed that tRF-16-R29P4PE minic improved cardiac function, reduced myocardial fibrosis, and mitigated metabolic disorders and mitochondrial damage. Furthermore, co-immunoprecipitation (Co-IP) and molecular docking assays confirmed a direct interaction between PACE4 and HIF-1α, and luciferase reporter assays identified PACE4 as a direct target of tRF-16-R29P4PE. By regulating the PACE4 and HIF-1α/PPARα signaling pathways, tRF-16-R29P4PE alleviates PCH, providing a promising molecular target for therapeutic intervention.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119920"},"PeriodicalIF":4.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413296","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":"Connexin 43 dephosphorylation mediates the Dchs1/YAP/TEAD signaling pathway to induce cardiac fibrosis","authors":"Min Wang ,&nbsp;Wanning Li ,&nbsp;Yaqing Shao ,&nbsp;Feng Wang ,&nbsp;Ying Huang ,&nbsp;Chenchen Wei ,&nbsp;Ping Li ,&nbsp;Kangyun Sun ,&nbsp;Xinxin Yan ,&nbsp;Zhongshan Gou","doi":"10.1016/j.bbamcr.2025.119919","DOIUrl":"10.1016/j.bbamcr.2025.119919","url":null,"abstract":"<div><h3>Background</h3><div>The gap junction protein connexin 43 (Cx43) has been implicated in the development of cardiac fibrosis. Our previous findings revealed that Cx43 dephosphorylation at serine 282 (S282) is related to cardiomyocyte apoptosis and arrhythmias in hearts damaged by ischemia/reperfusion. In this study, we investigated the role of Cx43 S282 phosphorylation in cardiac fibrosis.</div></div><div><h3>Methods</h3><div>We used angiotensin II (Ang II) intervention in mice to establish an in vivo cardiac fibrosis model and transforming growth factor β-1 (TGF-β1) intervention in cardiac myofibroblasts to establish an in vitro fibrosis model. The expression of Cx43 S282 phosphorylation was examined in the in vivo and in vitro models. To further confirm the effect of Cx43 S282 phosphorylation on cardiac fibrosis, we transfected cardiac myofibroblasts with lentiviral bodies in vitro, and injected myocardium with adenovirus in vivo to establish the over-expression of phosphorylation of Cx43 S282 locus and mutant groups. We sequenced the mRNA of the in vitro group using gene set enrichment analysis (GSEA) and normalized enrichment scoring (NES) to investigate the signaling pathway by which p282-Cx43 affects myocardial fibrosis (MF). The role of the Hippo signaling pathway in phosphorylation at the Cx43 282 site was further validated.</div></div><div><h3>Results</h3><div>In an in vivo and in vitro model of cardiac fibrosis, the level of phosphorylation of Cx43 S282 was reduced. Mutation of Cx43 S282 to a less phosphorylatable form (S282A) resulted in elevated levels of fibrosis markers, suggesting a critical antifibrotic role for phosphorylated Cx43 S282. Increased phosphorylation of Cx43 S282 produced an inhibitory effect on fibrosis. Enrichment analysis of mRNA sequencing in the mutant model group indicated that the Hippo signaling pathway was involved in the fibrosis process. Cx43 S282 phosphorylation increased the expression of Dchs1 gene, which activates the phosphorylation of yes-associated protein (YAP) and inhibits the YAP/TEAD signaling pathway to inhibit fibrosis development.</div></div><div><h3>Conclusions</h3><div>This study suggests that the phosphorylation of Cx43 S282 could be an effective antifibrotic target in cardiac fibroblasts. This indicates a novel mechanism and a molecular target that may hold promise for treating cardiac fibrosis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119919"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405607","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":"SIRT3 impairment and MnSOD hyperacetylation in trophoblast dysfunction and preeclampsia","authors":"Yangnan Ding,&nbsp;Xuewei Zhang,&nbsp;Jin Li,&nbsp;Yina Li,&nbsp;Linlin Zhang,&nbsp;Enwu Yuan","doi":"10.1016/j.bbamcr.2025.119915","DOIUrl":"10.1016/j.bbamcr.2025.119915","url":null,"abstract":"<div><div>Preeclampsia (PE) is a prevalent obstetric disorder that affects 2–8 % of pregnancies worldwide. Trophoblasts, which are crucial functional cells in the placenta, play a significant role in the development of PE due to inadequate invasion. Sirtuin 3 (SIRT3) is an NAD⁺ − dependent mitochondrial deacetylase, that positively modulates energy metabolism, mitochondrial biogenesis, and protection against oxidative stress. However, the role of SIRT3 in trophoblast dysfunction and the pathogenesis of PE remains unclear. In this study, we aim to investigate the functional role of SIRT3 in PE and explore the underlying mechanism. Our results demonstrated that human PE placentas exhibited reduced expression of SIRT3. <em>In vitro</em> experiments showed that hypoxia promoted SIRT3 expression, while oxidative stress inhibited SIRT3 expression in HTR-8/SVneo cells. The reduced SIRT3 expression inhibited the proliferation and migration of trophoblast cells while also increasing levels of reactive oxygen species and inflammatory factors. As a deacetylase, SIRT3 deficiency increased the acetylation level of manganese superoxide dismutase (MnSOD), a key mitochondrial antioxidant enzyme, subsequently reducing its activity. These effects associated with reduced SIRT3 expression could be reversed by treatment with MnSOD mimetics TEMPO and overexpression of MnSOD. All these results suggested that diminished SIRT3 expression leaded to MnSOD hyperacetylation and inactivation, contributing to trophoblast dysfunction and the pathogenesis of PE.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119915"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143395690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A","authors":"Junji Tao ,&nbsp;Yuanyuan Liu ,&nbsp;Xin Tang ,&nbsp;Dan Nie ,&nbsp;Kang Wu ,&nbsp;Kai Wang ,&nbsp;Ni Tang","doi":"10.1016/j.bbamcr.2025.119916","DOIUrl":"10.1016/j.bbamcr.2025.119916","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality globally, with hypoxia recognized as a key factor in its progression. Solute carrier family 27 member 5 (SLC27A5/FATP5), a pivotal enzyme in hepatic fatty acid transport and bile acid metabolism, is frequently downregulated in hepatocellular carcinoma, resulting in poor prognosis. However, the link between hypoxia and the suppression of SLC27A5 in HCC remains to be elucidated. Here, we investigated the hypoxia-induced downregulation of SLC27A5 and its impact on HCC proliferation via the repression of hepatocyte nuclear factor 4 alpha (HNF4A). Utilizing in vitro and in vivo hepatocellular carcinoma models, we have demonstrated that hypoxic conditions significantly reduce SLC27A5 transcription, which is mediated by the suppression of HNF4A. This reduction leads to the activation of the AKT pathway and an increase in cyclin-dependent kinase 2 (CDK2) and Cyclin E1 (CCNE1) expression, promoting the transition from the G1 to S phase of the cell cycle and driving HCC proliferation. Furthermore, we show that the pharmacological activation of HNF4A using Benfluorex, in combination with the AKT inhibitor MK2206, significantly inhibits tumor growth in a subcutaneous MHCC-97H xenograft model, suggesting a synergistic therapeutic potential. Together, our study provides novel insights into the hypoxia-mediated regulatory mechanisms in HCC and highlights the HNF4A/SLC27A5/AKT axis as a promising target for combination therapy.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119916"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387835","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}