Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"B7-H3-mediated deubiquitination stabilizing CYP1B1 expression promotes chemotherapy resistance in colorectal cancer","authors":"Huan Liu ,&nbsp;Guifang Li ,&nbsp;Chenjie Shen ,&nbsp;Xiaowei Qi ,&nbsp;Yankui Liu ,&nbsp;Dong Hua ,&nbsp;Yong Mao ,&nbsp;Ting Zhang","doi":"10.1016/j.bbadis.2025.167771","DOIUrl":"10.1016/j.bbadis.2025.167771","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is the second‑leading cause of cancer-related mortality worldwide. It is frequently characterized by chemotherapy resistance，which is a predominant factor contributing to unfavorable patient prognosis. B7-H3 is a novel tumor marker and a potential immunotherapy target. High B7-H3 expression in colorectal cancer is associated with adverse prognosis. In this study, we noted increased B7-H3 expression in colorectal cancer tumor tissues. Both in vivo and in vitro experiments demonstrated that increased B7-H3 expression promotes resistance to chemotherapy in CRC. Furthermore, our findings suggest that B7-H3 mediates CRC resistance by modulating CYP1B1 expression. Mechanistic investigations indicated that B7-H3 inhibited the ubiquitination of CYP1B1, stabilized its expression，and consequently enhanced chemotherapeutic resistance in CRC. In summary, our results underscore the significance of the B7-H3-CYP1B1 interaction as a crucial therapeutic target for overcoming chemotherapy resistance in CRC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167771"},"PeriodicalIF":4.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588636","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":"Ischemia-reperfusion injury induces ZBP1-dependent PANoptosis in endothelial cells","authors":"Yue Cui ,&nbsp;Huang Lin ,&nbsp;Jiaxing Ma ,&nbsp;Yinhua Zhao ,&nbsp;Jiaxi Li ,&nbsp;Yang Wang ,&nbsp;Jingwei Zhuang ,&nbsp;Yu Yang","doi":"10.1016/j.bbadis.2025.167782","DOIUrl":"10.1016/j.bbadis.2025.167782","url":null,"abstract":"<div><div>Endothelial cells play a critical role in the pathophysiology of ischemia-reperfusion injury (IRI). Although previous studies have shown that IRI can activate PANoptosis, the underlying mechanisms remain unclear. Our research investigates how IRI induces PANoptosis in endothelial cells, aiming to identify protective strategies to safeguard these cells from PANoptosis triggered by IRI. We established an in vitro endothelial cell hypoxia/reoxygenation (H/R) treatment model and an in vivo SD rat free flap IRI model. A series of assays, including PI/Hoechst staining, Western blotting, and immunohistochemistry, were conducted to assess PANoptosis-like cell death in endothelial cells. Cell transfection with ZBP1 siRNA and immunoprecipitation were used to explore the involved signaling pathways. Our results showed activation of PANoptosis-like cell death and upregulation of ZBP1 expression following IRI. After knocking down ZBP1 expression, a significant alteration in PANoptosis-like cell death and the assembly of the ZBP1-PANoptosome in endothelial cells was observed, confirming the occurrence of PANoptosis. In conclusion, our research confirms that IRI induces PANoptosome formation, promoting ZBP1-dependent PANoptosis in endothelial cells.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167782"},"PeriodicalIF":4.2,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588724","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":"Cell competition as an emerging mechanism and therapeutic target in cancer","authors":"Dakai Yang ,&nbsp;Wenyue Sun ,&nbsp;Lu Gao ,&nbsp;Kai Zhao ,&nbsp;Qin Zhuang ,&nbsp;Yun Cai","doi":"10.1016/j.bbadis.2025.167769","DOIUrl":"10.1016/j.bbadis.2025.167769","url":null,"abstract":"<div><div>Cell competition, as an internal quality control mechanism that constantly monitor cell fitness and eliminate unfit cells, maintains proper embryogenesis and tissue integrity during early development and adult homeostasis. Recent studies have revealed that cell competition functions as a tumor-suppressive mechanism to defend against cancer by removing neoplastic cell, which however, is hijacked by tumor cells and drive cell competition in favor of mutant cells, thereby promoting cancer initiation and progression. In this review, with a special focus on mammalian systems, we discuss the latest insights into the mechanisms regulating cell competition and its dual role in tumor development. We also provide current strategies to modulate the direction of cell competition for the prevention and treatment of cancers.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167769"},"PeriodicalIF":4.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588658","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":"Update in the molecular mechanism and biomarkers of diabetic retinopathy","authors":"Hui Zhu ,&nbsp;Bingqi Li ,&nbsp;Tao Huang ,&nbsp;Bin Wang ,&nbsp;Shuoyu Li ,&nbsp;Kuai Yu ,&nbsp;Liwei Cai ,&nbsp;Yuxin Ye ,&nbsp;Siyuan Chen ,&nbsp;Haotian Zhu ,&nbsp;Jin Xu ,&nbsp;Qinkang Lu ,&nbsp;Lindan Ji","doi":"10.1016/j.bbadis.2025.167758","DOIUrl":"10.1016/j.bbadis.2025.167758","url":null,"abstract":"<div><div>Diabetic retinopathy (DR) is a serious complication of diabetes caused by long-term hyperglycemia that leads to microvascular and neuronal damage in the retina. The molecular mechanisms of DR involve oxidative stress, inflammatory responses, neurodegenerative changes, and vascular dysfunction triggered by hyperglycemia. Oxidative stress activates multiple metabolic pathways, such as the polyol, hexosamine, and protein kinase C (PKC) pathways, resulting in the production of, which in turn promote the formation of advanced glycation end products (AGEs). These pathways exacerbate vascular endothelial damage and the release of inflammatory factors, activating inflammatory signaling pathways such as the NF-κB pathway, leading to retinal cell damage and apoptosis. Additionally, DR involves neurodegenerative changes, including the activation of glial cells, neuronal dysfunction, and cell death. Research on the multiomics molecular markers of DR has revealed complex mechanisms at the genetic, epigenetic, and transcriptional levels. Genome-wide association studies (GWASs) have identified multiple genetic loci associated with DR that are involved in metabolic and inflammatory pathways. Noncoding RNAs, such as miRNAs, circRNAs, and lncRNAs, participate in the development of DR by regulating gene expression. Proteomic, metabolomic and lipidomic analyses have revealed specific proteins, metabolites and lipid changes associated with DR, providing potential biomarkers for the early diagnosis and treatment of this disease. This review provides a comprehensive perspective for understanding the molecular network of DR and facilitates the exploration of innovative therapeutic approaches.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167758"},"PeriodicalIF":4.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552558","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":"Association of proteomics with lymph node metastasis in early gastric cancer patients","authors":"Botao Yan ,&nbsp;Xiaoyu Dong ,&nbsp;Zaizeng Wu ,&nbsp;Dexin Chen ,&nbsp;Wei Jiang ,&nbsp;Jiaxin Cheng ,&nbsp;Gang Chen ,&nbsp;Jun Yan","doi":"10.1016/j.bbadis.2025.167773","DOIUrl":"10.1016/j.bbadis.2025.167773","url":null,"abstract":"<div><div>Surgical decision making for early gastric cancer (EGC) is heavily influenced by its metastasis into the lymph nodes. Currently, the clinicopathological features of EGC cannot be used to accurately distinguish between EGC patients with and without lymph node metastasis. Our retrospective case-matching study included a total of 132 samples from 66 pairs of EGC patients with or without lymph node metastasis and conducted proteomic assays. By comparing the lymph node metastasis group and the nonmetastasis group, we found that two proteins, GABARAPL2 and NAV1, were significantly associated with lymph node metastasis in EGC patients. Our prediction model using protein biomarkers had good prediction accuracy, with an area under the curve (AUC) of 0.87, a sensitivity of 0.78, a specificity of 0.89, and an accuracy of 0.84, which can help distinguish between EGC patients with and without lymph node metastasis and guide the decision-making process for performing tailored surgery.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167773"},"PeriodicalIF":4.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552562","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":"Red blood cell proteomic profiling in mild and severe obstructive sleep apnea patients before and after positive airway pressure treatment","authors":"Cristina Valentim-Coelho ,&nbsp;Joana Saraiva ,&nbsp;Hugo Osório ,&nbsp;Marília Antunes ,&nbsp;Fátima Vaz ,&nbsp;Sofia Neves ,&nbsp;Paula Pinto ,&nbsp;Cristina Bárbara ,&nbsp;Deborah Penque","doi":"10.1016/j.bbadis.2025.167767","DOIUrl":"10.1016/j.bbadis.2025.167767","url":null,"abstract":"<div><div>Obstructive Sleep Apnea (OSA) is characterized by recurrent-episodes of apneas/hypopneas during sleep, leading to recurrent intermittent-hypoxia and sleep fragmentation. Non-treated OSA can result in cardiometabolic diseases.</div><div>In this study, we applied a shotgun-proteomics strategy to deeper investigate the red blood cell-(RBC) homeostasis regulation in the context of OSA-severity and their response to six months of positive airway pressure (PAP)-treatment. RBC-samples from patients with Mild/Severe-OSA before/after-PAP treatment and patients as simple-snoring controls were selected. The mass-spectrometry raw-data was analysed by MaxQuant for protein identification/quantification followed by statistical Linear Models-(LM) and Linear Mixed Models-(LMM) to investigate OSA-severity effect and interaction with PAP, respectively. The functional/biological network analysis were performed by DAVID-platform.</div><div>The results indicated that key-enzymes of the <em>Embden-Meyerhof-Parnas</em> (EMP)-glycolysis and pentose phosphate pathway-(PPP) were differentially changed in Severe-OSA, suggesting that the O₂-dependent metabolic flux through EMP and PPP maybe compromised in these cells due to severe intermittent hypoxia/reoxygenation-induced oxidative-stress events in these patients. The Rapoport-Luebering-glycolytic shunt showed a significant downregulation across OSA-severity maybe to increase hemoglobin-O₂ affinity to adapt to O₂ low availability in the lung, although EMP-glycolysis showed decreased only in Severe-OSA.</div><div>Proteins of the immunoproteasome were upregulated in Severe-OSA maybe to respond to severe oxidative-stress. In Mild-OSA, proteins related to the ubiquitination/neddylation-(Ub/Ned)-dependent proteasome system were upregulated.</div><div>After PAP, proteins of Glycolysis and Ub/Ned-dependent proteasome system showed reactivated in Severe-OSA. In Mild-OSA, PAP induced upregulation of immunoproteasome proteins, suggesting that this treatment may increase oxidative-stress in these patients. Once validated these proteins maybe candidate biomarkers for OSA or OSA-therapy response.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167767"},"PeriodicalIF":4.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552561","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":"Proteomic- and metabolomic-based mechanisms of androgen-mediated right ventricular maladaptive remodeling under pressure overload","authors":"Jing Zhang ,&nbsp;Xiaohan Qin ,&nbsp;Yuhan Qin ,&nbsp;Feng Qi ,&nbsp;Yufei Wang ,&nbsp;Jiameng Sun ,&nbsp;Li Yan ,&nbsp;Wei Sun ,&nbsp;Xiaoxiao Guo","doi":"10.1016/j.bbadis.2025.167768","DOIUrl":"10.1016/j.bbadis.2025.167768","url":null,"abstract":"<div><h3>Background</h3><div>Right ventricular (RV) maladaptive remodeling has been demonstrated to be more severe in males than in females under similar afterload, with androgen potentially involved. However, the mechanism remains unknown.</div></div><div><h3>Methods</h3><div>We performed RV proteomics and metabolomics in male and castrated rats with pulmonary artery banding (PAB) or sham surgery. The core pathway was tested in other sets of male, castrated male, and testosterone-replaced rats with and without pathway inhibitors administration and in RV remodeling patients. Metabolite verification was carried out by matching secondary spectra.</div></div><div><h3>Results</h3><div>With the same extent of increases in RV afterload, male PAB rats exhibited more pronounced RV hypertrophy and fibrosis than castrated PAB rats (<em>p</em> &lt; 0.05). The omics analysis indicated that pathways and functions related to oxidative stress were exhibited in the male group, with the platelet-derived growth factor (PDGF) pathway being among them. More proteins and metabolites associated with fatty acid metabolism were downregulated in males. Correlation analysis showed that PDGF receptor beta (PDGFRB) and signal transducer and activator of transcription 3 (STAT3) were negatively correlated with carnitine and reactive oxygen species scavenging metabolites only in male rats. The activation of the PDGF pathway was verified in testosterone-replaced PAB rats and male patients with RV remodeling. Treatments with PDGFRB inhibitor and STAT3 inhibitor could reverse RV maladaptive remodeling in male and testosterone-replaced PAB rats but not in castrated ones.</div></div><div><h3>Conclusions</h3><div>Androgen might exacerbate RV maladaptive remodeling via intensified oxidative stress and insufficient energy supply, with activating the PDGFRB-STAT3 signaling being one of the possible pathways.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167768"},"PeriodicalIF":4.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552363","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":"Both carvedilol and cimetidine alleviate cisplatin-induced nephrotoxicity via downregulating OCT2","authors":"Huan Wu ,&nbsp;Yichun Ning ,&nbsp;Zhaoxing Sun ,&nbsp;Ji Ji ,&nbsp;Min Lu ,&nbsp;Xiaoyan Jiao ,&nbsp;Xiaoliang Xu ,&nbsp;Xiaoqiang Ding ,&nbsp;Xin Cheng ,&nbsp;Xiaofang Yu","doi":"10.1016/j.bbadis.2025.167754","DOIUrl":"10.1016/j.bbadis.2025.167754","url":null,"abstract":"<div><h3>Background</h3><div>Cisplatin is a common chemotherapy agent for solid tumors but severe nephrotoxicity limits its application, with no effective pharmacological treatments. Organic cation transporter 2 (OCT2) is involved in cisplatin uptake in kidneys. This study aimed to find drugs with promising clinical applications that could prevent cisplatin-induced acute kidney injury (Cis-AKI) by inhibiting OCT2.</div></div><div><h3>Methods</h3><div>The mRNA level of OCT2 was examined in human induced pluripotent stem cells (iPSCs) from Cis-AKI patients and paired non-AKI patients. The association between OCT2 and Cis-AKI was investigated by HEK293FT cells and kidney organoids. We screened potential compounds exhibiting protective effects against Cis-AKI in US Food and Drug Administration-approved drugs through virtual screening and activity screening. Subsequently, we determined the effects of these compounds on OCT2 expression, cisplatin uptake, and apoptosis in cells, kidney organoids and mice. A549 and HeLa cells were adopted to observe the influence of drugs on the anti-tumor function of cisplatin.</div></div><div><h3>Results</h3><div>Compared to non-AKI patients, the OCT2 mRNA levels of iPSCs from Cis-AKI patients were elevated. OCT2 exhibits similar expression patterns in kidney organoids and human kidney tissues. Furthermore, the overexpression of OCT2 in kidney organoids and HEK293FT cells exacerbated the injury caused by cisplatin. Carvedilol and cimetidine were identified as potent OCT2 inhibitors by drug screening. Further analysis revealed that the pretreatment of carvedilol or cimetidine downregulated OCT2, reduced cisplatin uptake, and alleviated cisplatin-induced apoptosis, but the combination of the two drugs didn't further improve these outcomes. Additionally, carvedilol and cimetidine didn't compromise the cisplatin-induced cell death in A549 and HeLa cells.</div></div><div><h3>Conclusion</h3><div>Our study confirmed that carvedilol and cimetidine exert protective effects against Cis-AKI by inhibiting OCT2, without altering the anti-tumor effects of cisplatin.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167754"},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569283","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":"HDCA6 suppresses GATA6 expression to enhance cellular growth and migration in lung squamous cell carcinoma","authors":"Changhua Huang ,&nbsp;Hua Yang ,&nbsp;Hailong Wang ,&nbsp;Shouyin Sheng ,&nbsp;Limin Chen","doi":"10.1016/j.bbadis.2025.167757","DOIUrl":"10.1016/j.bbadis.2025.167757","url":null,"abstract":"<div><h3>Background</h3><div>Lung squamous cell carcinoma (LUSC) exhibits a significant mortality rate and lacks effective targeted therapies. The GATA-binding factor 6 (GATA6), a pivotal regulator of lung development, undergoes reduced expression in LUSC and correlates with its metastasis and prognosis. However, the regulatory mechanisms underlying the down-regulation of GATA6 in LUSC remain elusive. HDAC6 emerges as a promising therapeutic target in preclinical cancer models. Nevertheless, its role in LUSC progression remains unexplored. Furthermore, the regulatory impact of HDAC6 on GATA6 expression needs clarification. The purpose of this work is to investigate HDAC6's involvement and regulatory mechanisms on the expression of GATA6 in LUSC.</div></div><div><h3>Methods</h3><div>The impacts of HDCA6 on the expression of GATA6 were assessed using qPCR, Western blot and CHIP assays. The tumorigenic capacity of HDAC6 in promoting the growth and migration of LUSC cell were determined through CCK8, EdU incorporation, Transwell, and xenograft tumor models. Immunohistochemistry assays were employed to detected expression of HDAC6 in tissue microarray of LUSC.</div></div><div><h3>Results</h3><div>A pan-HDACs inhibitor Trichostatin A and an HDAC6-specific inhibitor CAY10603 up-regulate the expression of GATA6, whereas HDAC6 overexpression down-regulates GATA6 level. Overexpression of HDAC6 promotes cell proliferation and migration in LUSC, while inhibition of HDAC6 significantly suppresses LUSC cell growth. And, GATA6 overexpression reverses HDAC6-mediated elevated growth and migration of LUSC cells. Compared to normal tissues, LUSC tissues exhibit elevated levels of HDAC6 expression, which were correlated with poor prognosis of LUSC patients.</div></div><div><h3>Conclusion</h3><div>Targeting HDAC6/GATA6 pathway may offer promising prospects for developing of novel therapeutic strategies against LUSC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167757"},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143562260","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":"Cardioprotective potential of transcription factor PRRX1 silencing against myocardial ischemia/reperfusion injury by regulating excessive mitophagy and ferroptosis through FKBP5-p38 MAPK axis","authors":"Yongpeng Fang ,&nbsp;Xudong Niu ,&nbsp;Weifang Zhao ,&nbsp;Huali Zhang","doi":"10.1016/j.bbadis.2025.167766","DOIUrl":"10.1016/j.bbadis.2025.167766","url":null,"abstract":"<div><div>Myocardial ischemia/reperfusion (I/R) injury is a major cause of various adverse cardiovascular outcomes associated with excessive mitophagy and cardiomyocyte ferroptosis. Paired-related homeobox 1 (PRRX1) is a transcriptional factor involved in cardiovascular injury. However, whether and how PRRX1 regulates excessive mitophagy and cardiomyocyte ferroptosis during myocardial I/R injury remains unclear. Oxygen-glucose deprivation and reperfusion (OGD/R)-treated AC16 cardiomyocytes and myocardial I/R-induced rats were used as in vitro and in vivo models. Our results showed that PRRX1 expression was upregulated in AC16 cells after OGD/R treatment. PRRX1 silencing mitigated OGD/R-induced excessive mitophagy by increasing the mitochondrial membrane potential, adenosine triphosphate and p62 levels, and reducing LC3 II/I level in AC16 cells. In addition, PRRX1 knockdown attenuated OGD/R-induced lactate dehydrogenase (LDH) release and cardiomyocyte ferroptosis by decreasing reactive oxygen species, Fe²⁺ and acyl-CoA synthetase long-chain family member 4 (ACSL4) levels, and increasing glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels. Furthermore, PRRX1 transcriptionally promoted FK506 binding protein 5 (FKBP5), and increased p38 MAPK activation in AC16 cells. FKBP5 overexpression reversed the effects of PRRX1 silencing on excessive mitophagy and cardiomyocyte ferroptosis in OGD/R-treated AC16 cells. These effects were mitigated by a p38 MAPK inhibitor. Finally, PRRX1 downregulation mitigated myocardial I/R injury by reducing heart infarction and creatine kinase-myocardial band (CK-MB) levels in rat models. These findings demonstrate that PRRX1 silencing attenuates OGD/R-induced excessive mitophagy and cardiomyocyte ferroptosis by decreasing FKBP5 expression and inactivating p38 MAPK signaling, indicating the cardioprotective potential of PRRX1 silencing in myocardial I/R injury.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 5","pages":"Article 167766"},"PeriodicalIF":4.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552556","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}