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by claude@2026-07, 2026-07-05
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The study investigated lipid metabolic gene programs in metabolic-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) and how long-chain acyl-CoA synthetases (ACSLs) relate to ferroptosis, using integrated bulk RNA-seq, single-cell RNA-seq, spatial transcriptomics, and immunohistochemistry in human MASH-HCC, alongside in vitro ferroptosis assays in human HCC cell lines and single-cell ACSL characterization in a diet-induced murine MASH-HCC model. They found heterogeneous ACSL expression in human tumors, with ACSL4 enriched in tumor tissues and ACSL5 upregulated in non-cancerous MASH, and they identified a MASH-HCC lipid metabolic gene signature that included ferroptosis vulnerability genes. In vitro, ACSL4 upregulation correlated with increased ferroptosis sensitivity, and in the murine model elevated ACSL4 expression was detected in immune cells, suggesting a role in shaping the tumor immune microenvironment. A key caveat is that ferroptosis linkage was primarily demonstrated in HCC cell line experiments rather than directly in vivo, and the study is focused on transcriptomic associations and cell-based ferroptosis measures rather than definitive mechanistic causality. This paper is centrally about endometriosis/adenomyosis only in the sense that it does not explicitly discuss either condition; it was included in the corpus via a keyword match in the upstream search index.
Abstract
ABSTRACT Metabolic-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) incidence is rapidly rising worldwide. Lipid metabolic reprogramming is a hallmark of solid tumors to satisfy cancer high metabolic demand. However, it may confer sensitivity to ferroptosis, a cell death mode driven by iron-dependent lipid peroxidation. In this report, we describe the lipid metabolic landscape in MASH-HCC and characterize long chain acyl-CoA synthetases (ACSLs), a family of enzymes involved in synthesis of cellular lipids. Bulk RNA-sequencing, single-cell RNA-sequencing, spatial transcriptomics and immunohistochemistry analyses of human MASH-HCC were integrated to identify differentially expressed lipid metabolism genes. Ferroptosis in vitro was assessed in human HCC cell lines. A characterization of ACSLs was also conducted at the single-cell level in a diet-induced experimental murine model of MASH-HCC. Our analysis revealed that in human MASH-HCC, ACSLs exhibit a heterogeneous expression, with ACSL4 notably enriched in tumor tissues, contrasting with ACSL5 upregulation in non-cancerous MASH. We identified a unique lipid metabolic gene signature of MASH-HCC, which included genes associated with ferroptosis vulnerability. In vitro , ACSL4 upregulation was associated with increased ferroptosis sensitivity in human HCC cell lines. Lastly, single-cell RNA-sequencing revealed elevated ACSL4 expression in immune cells in a murine MASH-HCC model, suggesting a role of ACSL4 in shaping the tumor immune microenvironment. Overall, this report offers new insights into lipid metabolic landscape and ferroptosis sensitivity for novel MASH-HCC treatments. GRAPHICAL ABSTRACT
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ABSTRACT
Metabolic-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) incidence is rapidly rising worldwide. Lipid metabolic reprogramming is a hallmark of solid tumors to satisfy cancer high metabolic demand. However, it may confer sensitivity to ferroptosis, a cell death mode driven by iron-dependent lipid peroxidation. In this report, we describe the lipid metabolic landscape in MASH-HCC and characterize long chain acyl-CoA synthetases (ACSLs), a family of enzymes involved in synthesis of cellular lipids. Bulk RNA-sequencing, single-cell RNA-sequencing, spatial transcriptomics and immunohistochemistry analyses of human MASH-HCC were integrated to identify differentially expressed lipid metabolism genes. Ferroptosis in vitro was assessed in human HCC cell lines. A characterization of ACSLs was also conducted at the single-cell level in a diet-induced experimental murine model of MASH-HCC. Our analysis revealed that in human MASH-HCC, ACSLs exhibit a heterogeneous expression, with ACSL4 notably enriched in tumor tissues, contrasting with ACSL5 upregulation in non-cancerous MASH. We identified a unique lipid metabolic gene signature of MASH-HCC, which included genes associated with ferroptosis vulnerability. In vitro, ACSL4 upregulation was associated with increased ferroptosis sensitivity in human HCC cell lines. Lastly, single-cell RNA-sequencing revealed elevated ACSL4 expression in immune cells in a murine MASH-HCC model, suggesting a role of ACSL4 in shaping the tumor immune microenvironment. Overall, this report offers new insights into lipid metabolic landscape and ferroptosis sensitivity for novel MASH-HCC treatments.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Financial Support: This study was supported by the Mayo Clinic Center for Biomedical Discovery Pilot Award and NCI-funded Mayo Clinic SPORE in Hepatobiliary Cancer (P50 CA210964) Career Enhancement Program to DP.
Conflict of Interest: None to disclose
ABBREVIATIONS
- MASLD
- Metabolic-dysfunction associated steatotic liver disease
- MASL
- Metabolic-dysfunction associated steatotic liver
- MASH
- Metabolic-dysfunction associated steatohepatitis
- HCC
- Hepatocellular carcinoma
- MASH-HCC
- MASH-driven hepatocellular carcinoma
- PUFA-PL
- Polyunsaturated fatty acid-containing membrane phospholipids
- GPX4
- Glutathione peroxidase 4
- FSP1
- Ferroptosis suppressor protein 1
- ACSLs
- Acyl-CoA synthetase long chain
- NK
- natural killer cells
- NKT
- natural killer T cells
- IRB
- Institutional Review Board
- scRNA
- single-cell RNA
- DEGs
- differentially expressed genes
- cDNA
- Complementary DNA
- RT-qPCR
- Real-time quantitative polymerase chain reaction
- FFPE
- Formalin-fixed paraffin-embedded
- H&E
- Hematoxylin and eosin
- GPC3
- Glypican-3
- FBS
- fetal bovine serum
- SDS-PAGE
- SDS-polyacrylamide gel electrophoresis
- HRP
- horseradish peroxidase
- CO2
- Carbon dioxide
- WD
- Western diet
- CCl4
- Carbon tetrachloride
- PUFA
- polyunsaturated fatty acids
- SFA
- Saturated fatty acids
- MUFA
- Monounsaturated fatty acids
- UMAP
- Uniform manifold approximation and projection
- AKR1C3
- Aldo-keto reductase family 1 member C3
- GC
- group-specific component
- SPINK1
- serine protease inhibitor Kazal type 1
- ELOVL2
- elongation of very long chain fatty acids-like 2
- PLA2G2A
- phospholipase A2 group IIA
- FASN
- fatty acid synthase
- FABP1
- fatty acid binding protein 1
- APOA2
- apolipoprotein A-II
- LPCAT3
- lysophosphatidylcholine acyltransferase 3
- FABP4
- fatty acid binding protein 4
- RSL3
- RAS-selective lethal 3
- DC
- Dendritic cells
- Treg
- T regulatory cells
- qHSC
- quiescent hepatic stellate cells
- FAO
- fatty acid oxidation
- LCFA
- long-chain fatty acids
- VLDL
- very low-density lipoprotein
- G0S2
- G0/G1 switch gene 2
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