Liver-originated selective autophagy of BTD by alectinib underlies concurrent hepatotoxicity and dermatotoxicity.

Alectinib serves as an indispensable treatment for ALK (ALK receptor tyrosine kinase)-positive non-small-cell lung cancer (NSCLC), yet its hepatotoxicity and dermatotoxicity pose significant clinical concerns due to poorly understood mechanisms. This study demonstrated that alectinib-induced dermatotoxicity was secondary to hepatotoxicity. Integrated multi-omics analysis revealed that alectinib triggered excessive macroautophagic/autophagic degradation of hepatic BTD (biotinidase), causing systemic biotin deficiency that drove both hepatocyte apoptosis and skin barrier dysfunction. Mechanistically, we discovered increased phosphorylation of NBR1 at Ser656, a previously uncharacterized site, which conferred protein stability and contributed to selective BTD degradation. Importantly, exogenous biotin supplementation concurrently mitigated alectinib-induced hepatotoxicity and dermatotoxicity, providing a strategy for safer clinical application. These results uncovered a novel paradigm in drug-induced multi-organ toxicity, in which dysregulated inter-organ crosstalk served as a central mechanistic element.