Hepatocellular Carcinoma Overcomes Lipid Depletion by Utilizing Serine for Phospholipid Synthesis and Enhanced Survival.

BACKGROUND & AIMS: Metabolic vulnerabilities of hepatocellular carcinoma (HCC) remain largely unexplored functionally, though their deregulation is a major cancer hallmark. This study aims to investigate HCC tumor cells marked lipid-dependency and explore their distinct responses when grown in lipid starved conditions.

METHODS

We challenged 8 HCC tumor cell lines by lipid depletion, studying their functional phenotypes through lipidomics, metabolomics, transcriptomics, and metabolic fluxes to define how tumor cells may survive metabolic challenges such as lipid depletion.

RESULTS

HCC cell lines were functionally grouped as lipid-depletion sensitive (LD-S), characterized by high triglycerides and cholesterol esters, or lipid-depletion resistant (LD-R), marked by increased membrane lipids like phosphatidylcholine and phosphatidylethanolamine. Separation of these cell models was based on ranked functional phenotypes, including clonogenicity (P<0.0001), population doubling time (P<0.01), viability (P<0.001), and senescence (P<0.01) in LD-S at acute 48-hour lipid starvation. During lipid depletion, LD-R tumor cells survive by promoting serine uptake (serine utilization, P<0.0001) and carbon-donor incorporation into their lipid synthesis pathways such as membrane lipids (P<0.05) and fatty acids (P<0.01). Based on the mechanistic difference between LD-S and LD-R models, a lipid-response signature consisting of 150 distinct genes was constructed, distinguishing 519 HCC patients into two subgroups based on their lipid-dependency genotypes, correlating LD-R traits with lower survival (P<0.0001), higher vascular invasion (P<0.001), and distinct immune compositions based on cell deconvolution and single cell transcriptomics.

CONCLUSIONS

Distinct sensitivity to lipid depletion underscores lipid metabolism as a therapeutic target offering new treatment options for HCC patients.

IMPACT AND IMPLICATIONS: This study shows that hepatocellular carcinoma displays distinct lipid metabolic dependencies, with some tumors being highly sensitive to lipid depletion while others adapt through increased membrane lipid synthesis and extracellular serine utilization. These findings highlight a potential vulnerability in HCC metabolic reprogramming, suggesting that targeting lipid and serine-dependent pathways may offer new therapeutic strategies. Although the MASLD-associated HCC sample size was limited, the work provides important insight into tumor heterogeneity and establishes a foundation for future basic and clinical studies aimed at exploiting metabolic weaknesses in HCC.