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

## TL;DR

The study reveals how L-carnitine and OCTN2 contribute to liver cancer progression and immunotherapy resistance through a non-canonical metabolic pathway.

## Contribution

Identifies a novel metabolic-epigenetic-immune bypass in MASH-HCC driven by L-carnitine and the LINCMD1/DZIP3/OCTN2 axis.

## Key findings

- L-carnitine redirects from fatty acid oxidation to acetyl group buffering in MASH-HCC, disrupting p53 and MHC-I pathways.
- LINCMD1 sequesters DZIP3 in the nucleus, stabilizing OCTN2 and amplifying L-carnitine accumulation.
- Targeting LINCMD1 with an LNP-delivered antisense oligonucleotide restores p53 and MHC-I function and enhances immunotherapy response.

## 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.

In non‐MASH‐HCC, L‐carnitine promotes tumor progression primarily through its classical role in enhancing fatty acid oxidation (FAO). However, in MASH‐HCC, where FAO is markedly suppressed, L‐carnitine shifts from this canonical function to serve instead as an intracellular acetyl group buffer. Elevated L‐carnitine in MASH‐HCC binds acetyl groups to form acetyl‐L‐carnitine, resulting in acetyl group depletion. This leads, on one hand, to reduced acetylation and decreased stability of the tumor suppressor p53, thereby compromising its tumor‐suppressive function and facilitating tumor progression. On the other hand, loss of histone H3 acetylation reduces activity, resulting in suppression of MHC‐I antigen presentation, which ultimately promotes immune evasion and resistance to immunotherapy. Mechanistically, the lncRNA LINCMD1 is highly expressed and predominantly localized in the nucleus of MASH‐HCC cells, where it binds to the E3 ubiquitin ligase DZIP3. This interaction retains DZIP3 within the nucleus, thereby reducing its interaction with the cytoplasmic carnitine transporter OCTN2, and inhibiting DZIP3‐mediated K48‐linked ubiquitination and proteasomal degradation of OCTN2. As a result, OCTN2 is stabilized and upregulated, leading to increased intracellular L‐carnitine accumulation and reinforcement of this non‐canonical metabolic pathway. (Created with bioRender.com)