In this report, we show that, in a NASH-like metabolic context with acute oxidative damage and hyper-efficient SREBP activation, despite the collateral cost of increased hepatic lipid deposition, INSIG1 deficiency leads to a beneficial outcome in NASH driven by an increase in desaturase activity and lipid remodelling as well as a multifaceted regulation of multiple metabolic pathways preventing hepatic lipotoxicity. The gene discussed is INSIG1; the disease is metabolic dysfunction-associated steatohepatitis.