Ferritinophagy activation and sideroflexin1-dependent mitochondrial iron overload contribute to patulin-induced cardiac inflammation and fibrosis.

Patulin (PAT) is a mycotoxin that is commonly present throughout the ecosystem where fungi grow and mainly contaminates food, soil, and water. PAT was found to be cardiotoxic in previous studies. However, the detailed mechanism has not been fully elucidated. The present study aimed to explore the role and underlying mechanism of ferroptosis in PAT-induced cardiac injury. Here, we confirmed in vivo and in vitro that ferroptosis is involved in PAT-induced myocardial inflammation and fibrosis. Mice exposed to PAT (1 and 2 mg/kg body weight/day for 14 days) exhibited myocardial inflammation and fibrosis along with disrupted iron homeostasis, elevated lipid peroxidation, depletion of glutathione peroxidase 4, and abnormal mitochondrial morphology. When primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells were exposed to PAT, ferroptosis was initiated in a dose-dependent manner, and this process could be significantly attenuated by ferrostatin-1. Mechanistically, we found that nuclear receptor coactivator (NCOA) 4, a master regulator of ferritinophagy, bound to and degraded ferritin in response to PAT treatment, thereby releasing large amounts of ferrous iron and further leading to sideroflexin (SFXN) 1-dependent mitochondrial iron overload. Conversely, knockdown of NCOA4 or SFXN1 with small interfering RNAs could effectively ameliorate ferroptotic cell death, cellular or mitochondrial iron overload and lipid peroxides accumulation. Furthermore, myocardial inflammation and fibrosis in PAT-exposed mice was alleviated by the mitochondrial iron chelator deferiprone. Overall, our findings underscore that ferritinophagy activation and SFXN1-dependent mitochondrial iron overload play critical roles in PAT-induced myocardial ferroptosis and consequent cardiotoxicity.

SOCS3 Negatively Regulates Cardiac Hypertrophy via Targeting GRP78-Mediated ER Stress During Pressure Overload.

Pressure overload-induced hypertrophic remodeling is a critical pathological process leading to heart failure (HF). Suppressor of cytokine signaling-3 (SOCS3) has been demonstrated to protect against cardiac hypertrophy and dysfunction, but its mechanisms are largely unknown. Using primary cardiomyocytes and cardiac-specific SOCS3 knockout (SOCS3cko) or overexpression mice, we demonstrated that modulation of SOCS3 level influenced cardiomyocyte hypertrophy, apoptosis and cardiac dysfunction induced by hypertrophic stimuli. We found that glucose regulatory protein 78 (GRP78) was a direct target of SOCS3, and that overexpression of SOCS3 inhibited cardiomyocyte hypertrophy and apoptosis through promoting proteasomal degradation of GRP78, thereby inhibiting activation of endoplasmic reticulum (ER) stress and mitophagy in the heart. Thus, our results uncover SOCS3-GRP78-mediated ER stress as a novel mechanism in the transition from cardiac hypertrophy to HF induced by sustained pressure overload, and suggest that modulating this pathway may provide a new therapeutic approach for hypertrophic heart diseases.