Hepatic NIK Protects Against Ethanol-Induced Steatosis by Stabilizing INPP5B to Suppress PI3K/AKT/ACLY Lipogenesis

Alcohol-associated liver disease (ALD) imposes a major global health burden, yet lacks FDA-approved targeted therapies. While NF-?B-inducing kinase (NIK) is recognized for its dual roles in hepatic inflammation and lipid metabolism, its specific function in ALD pathogenesis remained incompletely defined. Contrary to its established protective role against high-fat diet-induced steatosis, this study reveals a paradoxical protective function of hepatic NIK in chronic ethanol-induced steatosis. We demonstrate that liver-specific NIK deficiency unexpectedly exacerbates hepatic steatosis in chronic ethanol-fed mice. This aggravation occurs via activation of the PI3K/AKT-ATP Citrate Lyase (ACLY) signaling pathway, promoting lipogenesis. Importantly, NIK overexpression reversed steatosis in deficient mice, independent of the non-canonical NF-?B effector p52. Mechanistically, proteomics and functional studies identified Inositol polyphosphate-5-phosphatase b (INPP5B), a negative PI3K/AKT regulator, as a key downstream target. NIK stabilizes INPP5B by suppressing its ubiquitination and enhancing its interaction with Adaptor protein APPL1, thereby inhibiting PI3K/AKT/ACLY signaling. These findings unveil a novel, kinase/scaffold-dependent role for NIK in mitigating ethanol-induced steatosis through INPP5B stabilization and highlight its context-dependent, double-sided effects in ALD progression, offering new insights for therapeutic strategies. Overall design: NIKF/F and NIKHKO mice were treated with the Lieber-DeCarli ethanol liquid diet containing 5% ethanol for 4 weeks