Exogenous Hydrogen Sulfide Promotes FAM134B-Mediated Endoplasmic Reticulum Autophagy and Inhibits Cell Aging by PERK–eIF2α and Improves Homocysteinemic Hypertensive-Induced Myocardial Fibrosis

Background: Hyperhomocysteinemia (HHCY) is a major cardiovascular risk factor closely associated with hypertension, myocardial fibrosis, and cardiac dysfunction; however, the underlying cellular mechanisms remain incompletely understood. Hydrogen sulfide (H2S) has emerged as an important cardioprotective gasotransmitter, yet the role of H2S in regulating endoplasmic reticulum (ER) stress and ER-phagy in HHCY-related cardiac remodeling remains unknown. Methods: Therefore, this study aimed to investigate the effects of exogenous H2S in a rat model of hyperhomocysteinemic hypertension and in H9c2 cells exposed to homocysteine and angiotensin II. Results: HHCY markedly increased blood pressure, exacerbated myocardial fibrosis, and promoted cardiomyocyte senescence, accompanied by activation of ER stress signaling and suppression of ER-phagy. Administration of H2S significantly alleviated these pathological changes, as evidenced by improved hemodynamic parameters, reduced collagen deposition, and decreased expression of senescence-associated markers. Mechanistically, H2S treatment attenuated activation of the Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK)–Eukaryotic Initiation Factor 2α (eIF2α) pathway and enhanced Family with Sequence Similarity 134, Member B (FAM134B)-dependent ER-phagy, as indicated by increased LC3-II accumulation and augmented colocalization of FAM134B with LC3. Furthermore, silencing FAM134B substantially blunted the ability of H2S to restore ER-phagy and suppress cellular senescence, supporting a critical role for FAM134B in mediating the protective effects of H2S. Conclusions: These findings demonstrate that exogenous H2S mitigates HHCY-induced myocardial remodeling, in part, by dampening PERK–eIF2α-associated ER stress and promoting FAM134B-mediated ER-phagy. This study provides mechanistic insight into the cardioprotective actions of H2S in hyperhomocysteinemic cardiac injury and identifies ER-phagy as a potential therapeutic target.