MiR-199a-5p aggravates hypoxia/reoxygenation-induced cardiomyocyte ferroptosis by blocking HSPB1–Keap1/Nrf2/ARE signaling

accumulation, lipid peroxidation, and glutathione depletion, whereas miR-199a-5p inhibition conferred significant protection against H/R-induced injury. Mechanistically, heat shock protein β‑1 (HSPB1) was identified as a direct downstream target of miR-199a-5p, with HSPB1 overexpression alleviating and its silencing aggravating ferroptotic responses under H/R conditions. Rescue assays further confirmed that HSPB1 mediates the pro-ferroptotic effects of miR-199a-5p. At the molecular level, the miR-199a-5p/HSPB1 axis regulated key ferroptosis-related proteins, including ACSL4, SLC7A11, and GPX4, and disrupted Keap1/Nrf2/ARE antioxidant signaling during H/R injury. Collectively, these findings indicate that miR-199a-5p aggravates H/R-induced cardiomyocyte ferroptosis by suppressing HSPB1 and impairing Nrf2-dependent antioxidant defense, suggesting that circulating miR-199a-5p may serve as a biomarker of myocardial injury and a potential therapeutic target in ischemic heart disease.