OCTN2 Activates a Non‐Canonical Carnitine Metabolic Pathway to Promote MASH‐HCC Progression and Immunotherapy Resistance

ABSTRACT Metabolic dysfunction‐associated steatohepatitis related hepatocellular carcinoma (MASH‐HCC) is a distinct HCC subtype characterized by lipid accumulation, impaired fatty acid oxidation (FAO), immune evasion, and resistance to immunotherapy. In this study, we observed elevated levels of L‐carnitine—a classical FAO activator—and its transporter OCTN2 in MASH‐HCC. Mechanistically, L‐carnitine is redirected from FAO promotion to buffering intracellular acetyl groups via conversion to acetyl‐L‐carnitine, leading to acetyl group depletion. This disrupts protein acetylation through two distinct pathways: reduced acetylation of p53 weakens its tumor‐suppressive signaling and promotes tumor progression, while decreased acetylation of histone H3 impairs MHC‐I antigen presentation, facilitating immune evasion. We further identified that the lncRNA LINCMD1 competitively bound the E3 ligase DZIP3, sequestering it in the nucleus and preventing its interaction with cytoplasmic OCTN2. This inhibited K48‐linked ubiquitination of OCTN2 and stabilized its protein expression, further amplifying L‐carnitine accumulation. To therapeutically target this axis, we developed a liver‐specific lipid nanoparticle (LNP)‐delivered antisense oligonucleotide against the DZIP3‐binding region of LINCMD1, which restored p53 and MHC‐I pathways and enhanced anti–PD‐1 efficacy in vivo. Together, our findings uncover a noncanonical carnitine‐driven metabolic–epigenetic–immune bypass in MASH‐HCC and identify the LINCMD1/DZIP3/OCTN2–L‐carnitine axis as a potential therapeutic target.