CoQ10 ameliorates hypoxia-induced ferroptosis by suppressing HMGB1 acetylation and release.

Intermittent hypoxia (IH), the core pathological hallmark of obstructive sleep apnea (OSA), elicits long-term cardiac redox imbalance and progressive myocardial dysfunction, yet specific, mechanism-targeted therapies to reverse OSA-associated heart injury remain largely unavailable. This research aimed to systematically unravel the redox-dependent signaling cascade driving IH-induced cardiomyocyte damage and clarify the protective mechanism of coenzyme Q10 (CoQ10), an endogenous antioxidant enriched in cardiac mitochondria. Single-cell RNA-seq profiling identified Fap-positive cardiac fibroblasts as the primary cellular source of intermittent hypoxia-induced high-mobility group box 1 (HMGB1), confirming fibroblast-cardiomyocyte paracrine communication as a critical amplifier of myocardial oxidative lesions. In AC16 human cardiomyocytes, cyclic IH severely disrupted mitochondrial structure and function, triggering massive reactive oxygen species (ROS) accumulation and excessive lipid peroxidation to initiate iron-dependent ferroptosis, accompanied by suppressed xCT/GPX4/FTH1 and elevated pro-ferroptotic ACSL4. IH also promoted HMGB1 hyperacetylation and subsequent nuclear-to-cytoplasmic translocation to activate the TLR4/NF-κB inflammatory pathway; HMGB1 gene silencing markedly attenuated all IH-triggered pathological phenotypes. Co-IP, ChIP-qPCR and dual-luciferase reporter assays biochemically validated the HMGB1/TLR4/NF-κB/xCT regulatory axis. Consistent in vitro cellular and in vivo mouse IH model data demonstrated that CoQ10 supplementation restores HDAC1/2 expression and enzymatic activity to constrain HMGB1 acetylation, thereby blocking downstream pro-inflammatory and ferroptotic signaling cascades. Collectively, our results confirm that CoQ10 effectively alleviates IH-mediated myocardial oxidative damage by inhibiting HMGB1 release, offering a promising redox-targeted therapeutic candidate for clinical intervention of OSA-related cardiovascular complications.