International journal of molecular medicine最新文献

{"title":"Liriodendrin alleviates myocardial ischemia‑reperfusion injury via partially attenuating apoptosis, inflammation and mitochondria damage in rats.","authors":"Bo Li, Wei-Wei Yang, Bo-Chen Yao, Qing-Liang Chen, Li-Li Zhao, Yan-Qiu Song, Nan Jiang, Zhi-Gang Guo","doi":"10.3892/ijmm.2025.5506","DOIUrl":"10.3892/ijmm.2025.5506","url":null,"abstract":"<p><p>Myocardial ischemia‑reperfusion (I/R) injury may lead to dysfunction of signaling pathways related to cell apoptosis, inflammation, oxidative stress, and mitochondrial damage. The present study investigated the defensive effect of liriodendrin, as a natural product isolated from <i>Linaria vulgaris</i>, on reperfusion injury in rats and the underlying mechanisms involved in this process. An <i>in vivo</i> rat model of I/R constructed by ligation of the left anterior descending artery, as well as an <i>in vitro</i> model using H9C2 cells under hypoxic conditions, was established to assess the cardioprotective effects of liriodendrin. The biomarkers of myocardial damage, oxidative stress, and inflammatory response were measured with enzyme‑linked immunosorbent assay (ELISA). Gene and protein expression were detected by reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. Mitochondrial morphology was observed by electron microscopy. The levels of creatine kinase isoenzymes and cardiac troponin T were significantly elevated in the I/R compared with the sham group; liriodendrin mitigated this elevation. The liriodendrin group exhibited a significant reduction in myocardial tissue apoptosis, as indicated by immunohistochemical staining and western blotting. Additionally, ELISA indicated that the I/R group had higher levels of reactive oxygen species (ROS) compared with the liriodendrin group, while the liriodendrin group had higher levels of superoxide dismutase. The <i>in vitro</i> experiments demonstrated that liriodendrin ameliorated hypoxia‑induced injury to mitochondria and suppressed the activation of nuclear factor-κB and B-cell lymphoma-2 associated X protein (Bax). Therefore, the present study demonstrated that liriodendrin impeded ROS‑associated metabolic disorders, maintained mitochondrial homeostasis and partially alleviated cardiomyocyte apoptosis by inhibiting the Bax signaling pathway.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 4","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR‑100: A key tumor suppressor regulatory factor in human malignant tumors (Review).","authors":"Liang Zhang, Jiuling Zhang, Xue Zhang, Shuang Liu, Chunyu Qi, Shengyu Gao","doi":"10.3892/ijmm.2025.5508","DOIUrl":"10.3892/ijmm.2025.5508","url":null,"abstract":"<p><p>MicroRNA (miRNA/miR)‑100 is a crucial tumor‑suppressive miRNA that serves a pivotal role in the initiation and progression of various malignancies. miR‑100 regulates cancer cell proliferation, migration, invasion and apoptosis by targeting oncogenes, and acts as a molecular sponge to regulate long non‑coding RNAs and circular RNAs, thereby influencing processes such as glycolysis, autophagy and resistance to chemotherapy/radiotherapy. Furthermore, miR‑100 suppresses tumor progression by modulating key signaling pathways, including the PI3K/AKT and Wnt/β‑catenin signaling pathways. miR‑100 exhibits potential for early cancer diagnosis, particularly in cancer types such as gastric and lung cancer, where it can serve as a non‑invasive biomarker for early screening. As a therapeutic target, restoring miR‑100 expression can enhance the efficacy of chemotherapy or targeted therapy, thereby improving patient prognosis. Although challenges remain in its clinical application, including delivery systems and safety concerns, ongoing research suggests that miR‑100 holds promise for personalized treatment and early diagnosis. Given that cancer remains a global health challenge, research on miR‑100 provides hope for cancer therapy, particularly in China, where the mortality rates of malignancies such as gastric, lung and liver cancer continue to rise, further emphasizing its potential for clinical translation.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 4","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular mechanisms underlying retinal ganglion cell apoptosis and optic nerve regeneration in glaucoma (Review).","authors":"Xiaotong Wang, Liang Sun, Xudong Han, Zhanglong Li, Yuqing Xing, Xinyue Chen, Ruofan Xi, Yuecong Sun, Guilong Wang, Ping Zhao","doi":"10.3892/ijmm.2025.5504","DOIUrl":"10.3892/ijmm.2025.5504","url":null,"abstract":"<p><p>Glaucoma is a neurodegenerative disease characterized by progressive and irreversible necrosis and apoptosis of retinal ganglion cells (RGCs). Deformation of the lamina cribrosa (LC) has been identified as a factor leading to damage to the optic nerve and capillaries passing through the LC, ultimately causing visual field defects and glaucoma development. Recent advancements in molecular biology, both domestically and internationally, have enabled a more comprehensive and in‑depth understanding of glaucoma pathogenesis. In the present review, the role of molecular signaling pathways associated with RGCs apoptosis, optic nerve protection and regeneration, and LC damage and remodeling in the development of glaucoma, are summarized and discussed. The insights provided herein may offer new targets and ideas for interventions and treatment strategies for glaucoma.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 4","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alda‑1 restores ALDH2‑mediated alcohol metabolism to inhibit the NF‑κB/VEGFC axis in head and neck cancer.","authors":"Yu-Hsuan Lin, Yi-Chen Lee, Jia-Bin Liao, Pei-Lun Yu, Chih-Yu Chou, Yi-Fang Yang","doi":"10.3892/ijmm.2025.5496","DOIUrl":"10.3892/ijmm.2025.5496","url":null,"abstract":"<p><p>The adaptation of cancer cells to hostile environments often necessitates metabolic pathway alterations to sustain proliferation and invasion. Head and neck cancer (HNC) has unfavorable outcomes. Therefore, elucidating the functional effects and molecular mechanisms underlying metabolic changes is key. Ingenuity Pathway Analysis identified 'ethanol degradation pathway II and IV' was consistently downregulated in tumor tissue, with aldehyde dehydrogenase 2 (<i>ALDH2</i>) emerging as a key prognostic gene among the top‑ranked differentially expressed metabolic pathways. Immunohistochemistry (IHC) of HNC specimens revealed significant downregulation of ALDH2 expression in tumor tissue, which was inversely correlated with T classification, overall stage, recurrence rate and independently predicted poor prognosis. Functional assays showed that ALDH2 knockdown enhanced HNC cell migration, invasion and colony formation, while ALDH2 overexpression attenuated these processes. Mechanistically, ALDH2 downregulation and subsequent reactive oxygen species (ROS) production in cells activated NF‑κB, upregulating vascular endothelial growth factor C (<i>VEGFC</i>) expression. ALDH2 overexpression inhibited ROS production and the NF‑κB/VEGFC oncogenic pathway, with pharmacological inhibition of NF‑κB and VEGFC mitigating the enhanced migration and invasion of ALDH2‑knockdown HNC cells. IHC and transcriptome analysis further highlighted an inverse association between ALDH2 and VEGFC, with the ALDH2^high/VEGFC^low profile predicting the most favorable survival outcome. Inhibition of ALDH2 with Daidzin increased <i>VEGFC</i> and phosphorylated NF‑κB levels, restoring the migration and invasion of ALDH2‑overexpressing HNC cells by enhancing the effects of VEGFC. Notably, modulating ALDH2 activity using Alda‑1 ameliorated NF‑kB/VEGFC axis upregulation following acetaldehyde treatment, aligning with the aforementioned alterations in alcohol metabolisms. These findings emphasize the key role of ALDH2 in influencing HNC progression and patient outcome, suggesting that targeting the ALDH2/NF‑κB/VEGFC pathway may represent a potential therapeutic strategy for HNC.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 4","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11819766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thymoquinone mitigates cardiac hypertrophy by activating adaptive autophagy via the PPAR‑γ/14‑3‑3γ pathway.","authors":"Rong-Bin Qiu, Shi-Tao Zhao, Zhi-Qiang Xu, Li-Juan Hu, Rui-Yuan Zeng, Zhi-Cong Qiu, Han-Zhi Peng, Lian-Fen Zhou, Yuan-Ping Cao, Li Wan","doi":"10.3892/ijmm.2025.5500","DOIUrl":"10.3892/ijmm.2025.5500","url":null,"abstract":"<p><p>Thymoquinone (TQ), the principal active compound derived from the black seed plant, has been extensively utilized in traditional medicine for treating various ailments. Despite its widespread use, its therapeutic mechanisms in the context of cardiac hypertrophy remain insufficiently understood. The present study focused on assessing the efficacy of TQ in mitigating cardiac hypertrophy while identifying its specific protective pathways. Through a combination of <i>in vivo</i> experiments utilizing a mouse model of transverse aortic constriction (TAC) and <i>in vitro</i> studies utilizing an angiotensin II (AngII)‑induced hypertrophy model in H9C2 cells, the protective actions of TQ were comprehensively evaluated. The results revealed that TQ significantly attenuated TAC‑induced cardiac hypertrophy and improved overall cardiac function. In AngII‑induced H9C2 cells, pretreatment with TQ significantly reduced both cell hypertrophy and reactive oxygen species levels, while simultaneously promoting autophagy and limiting fibrosis. TQ was also found to increase the transcriptional activity of peroxisome proliferator‑activated receptor‑γ (PPAR‑γ), which interacted with 14‑3‑3γ protein, leading to autophagy activation and subsequent cellular protection. However, the protective autophagic effects were attenuated when PPAR‑γ activity was inhibited alongside pAD/14‑3‑3γ‑short hairpin RNA administration. The present findings demonstrate that TQ mitigates cardiac hypertrophy by modulating autophagy via the PPAR‑γ/14‑3‑3γ signaling axis, highlighting its therapeutic potential for cardiac hypertrophy treatment.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 4","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[Corrigendum] Morroniside protects SK‑N‑SH human neuroblastoma cells against H₂O₂‑induced damage.","authors":"Jing-Xing Zhang, Rui Wang, Jin Xi, Lin Shen, An-You Zhu, Qi Qi, Qi-Yi Wang, Lun-Jun Zhang, Feng-Chao Wang, He-Zuo Lü, Jian-Guo Hu","doi":"10.3892/ijmm.2025.5501","DOIUrl":"10.3892/ijmm.2025.5501","url":null,"abstract":"<p><p>Following the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 2D on p. 606, which showed the results of cellular morphological experiments, two pairs of data panels were overlapping, such that data which were intended to show the results obtained under different experimental conditions may have been derived from the same original sources. The authors examined their original data, and realized that this figure had been assembled incorrectly (they were also able to send the data underlying this figure on to the Editorial Office for our inspection). The revised version of Fig. 2, now showing alternative data from one set of the repeated experiments, is shown on the next page. The authors confirm that the errors associated with this figure did not have any significant impact on either the results or the conclusions reported in this study, and all the authors agree with the publication of this Corrigendum. The authors are grateful to the Editor of <i>International Journal of Molecular Medicine</i> for granting them the opportunity to publish this Corrigendum; furthermore, they apologize to the readership of the Journal for any inconvenience caused. [International Journal of Molecular Medicine 39: 603‑612, 2017; DOI: 10.3892/ijmm.2017.2882].</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 4","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated neuregulin‑1 expression modulates tumor malignancy and autophagy in esophageal squamous cell carcinoma.","authors":"Yen-Chiang Tseng, Pei-Feng Liu, Yu-Ru Chen, Wen-Hsin Yang, Chia-Che Chang, Hsueh-Wei Chang, Cheng-Hsin Lee, Yih-Gang Goan, Chih-Wen Shu","doi":"10.3892/ijmm.2025.5503","DOIUrl":"10.3892/ijmm.2025.5503","url":null,"abstract":"<p><p>The 5‑year survival rate of patients with esophageal squamous cell carcinoma (ESCC) is <20%, highlighting the need for the development of novel therapeutic targets. Neuregulin‑1 (NRG1), a transmembrane protein involved in cell proliferation and survival signaling, has unclear biological functions and clinical value in ESCC. The present study investigated the association between NRG1 expression and ESCC by analyzing data from both patients with ESCC and The Cancer Genome Atlas database. Reverse transcription‑quantitative PCR and immunohistochemistry staining were used to determine the levels of gene and protein in the tissue. The findings revealed that NRG1 gene and protein levels were significantly higher in tumor tissues compared with the normal tissues. Elevated expression of NRG1 was associated with poor outcomes, particularly in patients with advanced ESCC. Silencing NRG1 decreased both its mRNA and protein levels, disrupting key signaling pathways, such as phosphorylated (p‑)AKT and cellular rapidly accelerated fibrosarcoma (p‑cRAF), which led to decreased cancer cell proliferation, migration and tumor sphere formation, along with increased cell death. High expression levels of NRG1 and cRAF were significantly associated with poor prognosis. Additionally, silencing NRG1 promoted autophagosome and autolysosome formation, decreasing LC3B levels. The use of the autophagy inhibitor chloroquine significantly enhanced cell death induced by NRG1 silencing, suggesting that autophagy functions as a survival mechanism in ESCC cells in which NRG1 is silenced. Furthermore, high co‑expression of NRG1 and LC3B was associated with a worse prognosis. On the whole, the present study demonstrated that targeting NRG1 with autophagy inhibitors may serve as a potential therapeutic strategy for ESCC.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 4","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin attenuates myocardial ischemia‑reperfusion‑induced autophagy‑dependent ferroptosis via Sirt1/AKT/FoxO3a signaling.","authors":"Shi-Tao Zhao, Zhi-Cong Qiu, Zhi-Qiang Xu, En-De Tao, Rong-Bin Qiu, Han-Zhi Peng, Lian-Fen Zhou, Rui-Yuan Zeng, Song-Qing Lai, Li Wan","doi":"10.3892/ijmm.2025.5492","DOIUrl":"10.3892/ijmm.2025.5492","url":null,"abstract":"<p><p>Curcumin (Cur) effectively attenuates myocardial ischemia/reperfusion injury (MIRI). MIRI has a complex mechanism and is associated with autophagy‑dependent ferroptosis. Therefore, the present study aimed to determine whether autophagy‑dependent ferroptosis occurs in MIRI and assess the mechanism of Cur in attenuating MIRI. The study was conducted on a Sprague‑Dawley rat MIRI model and H9c2 cell anoxia/reoxygenation (A/R) injury model. The effect of Cur pretreatment on A/R or MIRI induced autophagy‑dependent ferroptosis and its molecular mechanism were investigated. Protein expression, lysosomal, reactive oxygen species, Fe2+, oxidative systems, mitochondrial function, subcellular localization of molecules, and cardiac function assays will be employed. Cur decreased MIRI; improved myocardial histopathology; increased cardiomyocyte viability; inhibited ferroptosis, apoptosis and autophagy; reduced infarct size and maintained cardiac function. MIRI decreased silent information regulator 1 (Sirt1), decreased AKT and forkhead box O3A (FoxO3a) phosphorylation, leading to FoxO3a entry into the nucleus to activate translation of autophagy‑related genes and inducing ferroptosis, apoptosis and autophagy. However, Cur pretreatment activated AKT and FoxO3a phosphorylation via Sirt1, thereby transporting FoxO3a out of the nucleus, reducing autophagy‑related gene translation and attenuating MIRI‑induced ferroptosis, apoptosis and autophagy. Of note, the silencing of Sirt1 and administration of triciribine (an AKT inhibitor) both eliminated the protective effect of Cur. Thus, Cur maintained cardiomyocyte function by inhibiting autophagy‑dependent ferroptosis via Sirt1/AKT/FoxO3a signaling.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 3","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent insights and perspectives into the role of the miRNA‑29 family in innate immunity (Review).","authors":"Xing-Chen Yao, Jun-Jie Wu, Sheng-Tao Yuan, Feng-Lai Yuan","doi":"10.3892/ijmm.2025.5494","DOIUrl":"10.3892/ijmm.2025.5494","url":null,"abstract":"<p><p>Innate immunity is the first line of defence against pathogenic microorganisms and is nearly universal among eukaryotes. The innate immune system is composed of various organs, cells and immune molecules. MicroRNAs (miRs) are a class of small non‑coding RNAs (~22 nucleotides) that are widely involved in post‑transcriptional regulation of proteins within the innate immune system through the recognition of seed sequences. The present review summarizes the role of the miR‑29 family in innate immunity, with a focus on its specific functions in the differentiation of T cells, B cells, natural killer cells and macrophages, as well as the mechanisms by which the miR‑29 family participates in innate immune signalling. Additionally, this review discusses how the miR‑29 family helps the host combat infections by hepatitis B and C viruses, human immunodeficiency virus and influenza A virus through the regulation of specific signalling molecules. This comprehensive analysis of existing studies emphasizes the importance of the miR‑29 family in maintaining immune balance and defence against pathogens.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 3","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RGS12 is a target of penehyclidine hydrochloride that enhances oxidative stress and ferroptosis in a model of myocardial ischemia/reperfusion injury by inhibiting the Nrf2 pathway.","authors":"Congna Zi, Yulei Wei, Ying Zhu, Juan Fan","doi":"10.3892/ijmm.2025.5493","DOIUrl":"10.3892/ijmm.2025.5493","url":null,"abstract":"<p><p>Regulator of G‑protein signaling 12 (RGS12) is a regulatory factor that is involved in various physiological processes. However, the role of RGS12 in myocardial ischemia/reperfusion injury (MIRI) currently remains unclear. The present study established a mouse model of MIRI by ligating the left main coronary artery followed by reperfusion. In addition, mouse HL‑1 cells were cultured in a hypoxic and serum‑free medium, followed by reoxygenation to establish an <i>in vitro</i> cell model of hypoxia/reoxygenation (H/R). Adenoviruses targeting RGS12 were subsequently used to either overexpress or silence RGS12 expression. RGS12 was highly expressed in both the myocardial tissues of mice with MIRI and HL‑1 cells subjected to H/R. The results from the <i>in vitro</i> experiments demonstrated that the knockdown of RGS12 reduced oxidative stress under a pathological environment, as indicated by decreased reactive oxygen species (ROS) levels and malondialdehyde activity and increased activities of superoxide dismutase and catalase. Furthermore, mice with MIRI and HL‑1 cells that underwent H/R stimulation exhibited increased ferroptosis, whereas RGS12 knockdown reversed these changes. These results showed that post‑RGS12 silencing the levels of Fe²⁺ and lipid ROS were decreased, the expression levels of glutathione peroxidase 4 and cystine transporter solute carrier family 7 member 11 were increased and mitochondrial structure was improved by preventing the loss of the mitochondrial crest. Mechanistically, the nuclear factor erythroid 2‑related factor 2 (Nrf2) pathway with anti‑ferroptosis and anti‑oxidative stress capacities was activated by RGS12 knockdown. Conversely, RGS12 overexpression exerted the opposite effects both in vivo and in vitro. Notably, it was demonstrated that penehyclidine hydrochloride (PHC), known to block the MIRI process, decreased RGS12 expression levels both <i>in vivo</i> and <i>in vitro</i>, and RGS12 overexpression inhibited the therapeutic effects of PHC on MIRI. In conclusion, the present study demonstrated that RGS12, a target of PHC, potentially enhanced the progression of MIRI by promoting oxidative stress and ferroptosis, and this effect may involve the regulation of the Nrf2 pathway.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"55 3","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}