High insulin inhibits ferroptosis and alleviates acute lung injury via LNC473-HIF1α-GPX4/FSP1 axis in obese mice

<bold>Abstract</bold> <bold>Background:</bold> Obesity is a risk factor for Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS),but obesity is associated with lower mortality in patients with ALI/ARDS,a phenomenon known as the "Obesity Paradox",for which the underlying mechanisms are not fully understood. <bold>Objective:</bold> The study investigated the effects of obesity on ALI/ARDS and the roles of insulin and LNC473-HIF1α-GPX4/FSP1 axis in ferroptosis and their potential therapeutic effects in ALI/ARDS. <bold>Methods:</bold> Ferroptosis-related factors in mice with ALI or in BEAS-2B cells with LPS-induced injury were measured by western blotting, qPCR and immunohistochemical analysis. RIP,CHIP and Chromatin accessibility assays were used to investigate the correlation between LNC473 and HIF-1α.CHIP assays were employed to ascertain the correlation between HIF-1α and GPX4/FSP1. <bold>Results:</bold> In vivo, obesity inhibited ferroptosis and alleviated ALI. Inhibition of HIF-1α promoted ferroptosis and exacerbated ALI in obese mice. Inhibiting ferroptosis attenuated ALI in obese mice. Insulin attenuated LPS-induced BEAS-2B cell injury by inhibiting ferroptosis through upregulation of LNC473,HIF-1α,GPX4 and FSP1 expression. LNC473 attenuated BEAS-2B cell injury by inhibiting ferroptosis through epigenetically regulating HIF-1α.HIF-1α attenuated BEAS-2B cell injury by inhibiting ferroptosis through transcriptional regulation of GPX4/FSP1. <bold>Conclusions:</bold> The study found that obesity protects against ALI in mice and demonstrated that insulin promotes protection of the pulmonary epithelium by inhibiting ferroptosis through LNC473-HIF-1α-GPX4/FSP1 axis, which may be the underlying mechanisms of the "Obesity Paradox" in ALI/ARDS.