LZTR1 deficiency reprograms mitochondria via mtTFA stabilization to drive OXPHOS-dependent stemness and progression in HCC

Mitochondrial metabolic reprogramming is a hallmark of hepatocellular carcinoma (HCC), yet the mechanisms governing respiratory homeostasis in this malignancy remain incompletely understood. The adaptor protein leucine-zipper-like transcriptional regulator 1 (LZTR1) has been implicated in diverse cellular processes, but its role in mitochondrial regulation and HCC progression has not been defined. The tumor-suppressive function of LZTR1 was validated in vivo using subcutaneous/orthotopic HCC-derived models and hepatocyte-specific Lztr1 -knockout mice. The direct binding was confirmed by co-immunoprecipitation, fluorescence resonance energy transfer, proximity ligation assay, super-resolution structured illumination microscopy and molecular docking studies, with regulatory action evidenced by ubiquitination assays. Functional consequences were assessed through transcriptomic/proteomic profiling, transmission electron microscopy, and Seahorse assay. We identify LZTR1 as a pivotal suppressor of HCC. We demonstrate that YTHDF1 positively regulates LZTR1 translation in an m 6 A-dependent manner in HCC, and that low LZTR1 expression correlates with poor patient prognosis. Functional validation reveals that LZTR1 loss promotes stemness and tumor growth, and shifts metabolism toward complex I-dependent oxidative phosphorylation with concomitant redox stress. Mechanistically, LZTR1 binds mitochondrial transcription factor A (mtTFA) and directs K48-linked ubiquitination and proteasomal degradation prior to mitochondrial import, preventing mtTFA overaccumulation and excessive mtDNA transcription. Consequently, LZTR1 inactivation leads to mtTFA accumulation, driving a mtTFA-dependent phenotype that accelerates HCC initiation and progression while increasing sensitivity to complex I inhibition. Notably, most of the missense mutations we tested from liver tumors and Noonan syndrome failed to regulate mtTFA abundance. These findings define a mitochondrial quality-control checkpoint centered on LZTR1-mtTFA turnover that drives OXPHOS-dependent HCC progression, and expose a therapeutically exploitable vulnerability to complex I inhibition in LZTR1-deficient tumors. Upstream regulation of LZTR1 by the m 6 A reader YTHDF1 further integrates this axis into the epitranscriptomic network governing mitochondrial homeostasis.