NIK suppresses AKT/ACLY pathway-mediated lipogenesis in liver by stabilizing INPP5B during chronic ethanol exposure

Hepatic steatosis is a hallmark of alcohol-associated liver disease (ALD) and interacts with hepatic inflammation to drive disease progression. NF-κB-inducing kinase (NIK) has been established as a bridge linking inflammation to steatosis in ALD. Intriguingly, while hepatocyte-specific NIK deficiency attenuated ALD in the chronic-plus-binge model, it paradoxically exacerbated the disease under chronic ethanol exposure, suggesting a complex, context-dependent role for NIK.

To elucidate the mechanism underlying this protective effect in chronic ethanol exposure, we employed transcriptomics and proteomics analyses in hepatocyte-specific NIK knockout (NIK^Δhep) mice. Key findings were validated using immunoblotting, co-immunoprecipitation, and loss-of-function experiments both in vivo and in vitro.

We demonstrated that NIK deficiency activated AKT, enhancing ATP-citrate lyase (ACLY)-mediated lipogenesis. Transcriptomics and proteomic screening identified inositol polyphosphate-5-phosphatase B (INPP5B) as the critical mediator suppressing AKT signaling downstream of NIK. Furthermore, we mechanistically established that NIK stabilizes INPP5B by recruiting it into the adaptor protein APPL1 complex, thereby reducing its ubiquitination and subsequent degradation.

Our study unveils a novel protective dimension of NIK, whereby it ameliorates chronic ethanol-induced hepatic steatosis by stabilizing INPP5B to suppress the AKT/ACLY lipogenic pathway. This finding provides a crucial mechanistic explanation for the context-dependent functions of NIK in ALD and redefines its role as a potential metabolic safeguard in chronic liver disease.