Key result
APOLD1 overexpression alleviates hypoxia-induced cardiomyocyte damage and ferroptosis via Nrf2/HO-1 pathway activation.
Why the study?
Although APOLD1 is abnormally expressed in myocardial infarction models and inhibiting ferroptosis alleviates myocardial injury, the mechanism by which APOLD1 modulates ferroptosis in hypoxia-induced cardiomyocyte injury remained unclear.
Does APOLD1 overexpression or DNA methylation inhibition protect cardiomyocytes from hypoxia-induced ferroptosis via the Nrf2/HO-1 pathway in vitro?
Does APOLD1 overexpression or DNA methylation inhibition protect cardiomyocytes from hypoxia-induced ferroptosis via the Nrf2/HO-1 pathway in vitro?
This preclinical study identifies DNA methylation-regulated APOLD1 and the downstream Nrf2/HO-1 pathway as a potential molecular target for mitigating cardiomyocyte ferroptosis during hypoxic injury.
Answers are grounded in this paper and cite their sources.
APOLD1 ferroptosis modulation in MI models needs confirmation; leaves open any clinical relevance or therapeutic targeting.
Cardiomyocyte ferroptosis inhibition can alleviate myocardial injury during myocardial infarction (MI). Apolipoprotein L domain containing 1 (APOLD1) is abnormally expressed in the MI model. This study planned to elucidate the mechanism by which APOLD1 modulated ferroptosis in hypoxia-induced cardiomyocyte injury. The levels of myocardial injury markers, such as creatine kinase isoenzyme myocardial band, cardiac troponin T, and lactate dehydrogenase, were measured using ELISA kits. Cell death rate was determined utilizing flow cytometry with the Calcein-AM/PI kit. Intracellular Fe2+ level was examined using ELISA kits. Methylation-Specific PCR analysis was utilized to evaluate the CpG methylation status within the APOLD1 promoter. Chromatin immunoprecipitation assay was employed to confirm the interactions between APOLD1 and DNA methyltransferases (DNMTs). In this study, we found that the overexpressed APOLD1 alleviated cardiomyocyte damage and ferroptosis. Furthermore, APOLD1 activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway, which was involved in the APOLD1-mediated protection, by enhancing its nuclear translocation. Hypoxia inhibited APOLD1 expression via the promotion of DNMTs-mediated CpG methylation. The methylation inhibitor, 5-Azacytidine, ameliorated hypoxia-induced cardiomyocyte ferroptosis by restoring APOLD1 expression. Therefore, our data clarified that DNA methylation-modulated APOLD1 could alleviate ferroptosis by activating the Nrf2/HO-1 signaling in hypoxia-induced cardiomyocytes.
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Yuan et al. (2026) studied Hypoxia-induced cardiomyocyte injury (in vitro myocardial infarction model). APOLD1 overexpression and 5-Azacytidine (DNA methylation inhibitor) vs. Hypoxia-induced cardiomyocytes without APOLD1 overexpression or methylation inhibition was evaluated on Cardiomyocyte damage (CK-MB, cTnT, LDH), cell death rate, and intracellular Fe2+ levels (ferroptosis). Overexpression of APOLD1 or restoration of its expression via 5-Azacytidine alleviated hypoxia-induced cardiomyocyte damage and ferroptosis in vitro by activating the Nrf2/HO-1 pathway.
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