Alectinib通过肝脏BTD选择性自噬降解引发肝毒性和皮肤毒性的机制研究

Abstract

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.Abbreviations: AAV: adeno-associated virus; ALK: ALK receptor tyrosine kinase; BTD: biotinidase; c-CASP3: cleaved CASP3; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; DAPI: 4’,6-diamidino-2-phenylindole; DHE: dihydroethidium; ELISA: enzyme-linked immunosorbent assay; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic--pyruvic transaminase; GSEA: gene set enrichment analysis; H&E: hematoxylin and eosin; HPH: human primary hepatocyte; HRP: horseradish peroxidase; KEGG: Kyoto Encyclopedia of Genes and Genomes; KRT1: keratin 1; KRT5: keratin 5; KRT10: keratin 10; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPHs: mouse primary hepatocytes; MSEA: metabolite set enrichment analysis; OCR: oxygen consumption rates; PBS: phosphate-buffered saline; PCA: principal component analysis; PLS-DA: partial least squares discriminant analysi