Inhibition of ACLY enhances tumor immunogenicity and resolves MASH-driven HCC
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ABSTRACT:
PROVIDER: PRJNA1262480 | ENA |
REPOSITORIES: ENA
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Project description:Immunosuppressive tumor microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC). While immune cell metabolism influences effector function, the impact of tumor metabolism on immunogenicity is less understood. ATP citrate lyase (ACLY), a key enzyme linking catabolic and anabolic processes, supports lipid metabolism and gene regulation. Although ACLY inhibition shows anti-proliferative effects in various tumors, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways. Using a mouse model of MASH-driven HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumors reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 with cryo-EM structural analysis revealing EVT0185-CoA directly interacts with ACLY’s CoA binding site. Oral delivery of EVT0185 in four mouse models of MASH-HCC dramatically reduces tumor burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumor ACLY with increases in CXCL13, tumor infiltrating B-cells and tertiary lymphoid structures. Remarkably, the depletion of B cells blocked the anti-tumor effects of ACLY depletion. Together, these findings illustrate how targeting tumor metabolism can rewire immune function and suppress cancer progression in MASH-HCC.
2025-09-17 | GSE296668 | GEO
Project description:Inhibition of ACLY enhances tumor immunogenicity and resolves MASH-driven HCC
| PRJNA1260482 | ENA
Project description:Immunosuppressive tumor microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC). While immune cell metabolism influences effector function, the impact of tumor metabolism on immunogenicity is less understood. ATP citrate lyase (ACLY), a key enzyme linking catabolic and anabolic processes, supports lipid metabolism and gene regulation. Although ACLY inhibition shows anti-proliferative effects in various tumors, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways. Using a mouse model of MASH-driven HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumors reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 with cryo-EM structural analysis revealing EVT0185-CoA directly interacts with ACLY’s CoA binding site. Oral delivery of EVT0185 in four mouse models of MASH-HCC dramatically reduces tumor burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumor ACLY with increases in CXCL13, tumor infiltrating B-cells and tertiary lymphoid structures. Remarkably, the depletion of B cells blocked the anti-tumor effects of ACLY depletion. Together, these findings illustrate how targeting tumor metabolism can rewire immune function and suppress cancer progression in MASH-HCC.
2025-09-17 | GSE297190 | GEO
Project description:Immunosuppressive tumor microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma. To further investigate tumor–immune interactions, we performed spatial transcriptomics on livers from MASH-driven HCC mouse models (WD-DEN, WT or Acly KO mice and from WD-CCL4, Vehicle, or EVT0185 (100mg/kg) treated mice). GO enrichment analysis of spatially resolved tumor cells showed increased fatty acid and lipid metabolism in both Acly KO and EVT0185-treated mice Spatial analysis also revealed a selective increase in B cells, but not T cells, macrophages, or NKT cells, in tumors from Acly KO and EVT0185-treated mice.
2025-06-30 | GSE297081 | GEO
Project description:Inhibition of ACLY enhances tumor immunogenicity and resolves MASH-driven HCC [scRNA-seq]
| PRJNA1262969 | ENA
Project description:The alarming rise in the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is attributed significantly to dysregulated lipid metabolism. The present study discovered that a novel enedioic acid ACLY inhibitor 326E, an investigational new drug in Phase 2a study for hypercholesterolemia, markedly reduces hepatic lipid accumulation and alleviates MASH in two different mouse models of MASH. Mechanistic studies demonstrated that 326E exerts these effects not only by inhibiting ATP-citrate lyase (ACLY) to reduce de novo lipogenesis but also as a PPARα agonist to increase hepatic fatty acid oxidation with promoted mitochondrial biogenesis. Subsequent studies in cynomolgus monkeys (Macaca fascicularis) confirmed the effectiveness of 326E for MASH in primate species. In a randomized Phase 1b/2a clinical trial in MASH patients 326E was well tolerated and demonstrated a therapeutic potential for MASH signatures. Our results reveal a promising therapeutic potential of 326E for MASH via distinctive dual mechanisms of inhibiting ACLY while activating PPARα.
2025-10-17 | GSE279673 | GEO
Project description:The alarming rise in the prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is attributed significantly to dysregulated lipid metabolism. The present study discovered that a novel enedioic acid ACLY inhibitor 326E, an investigational new drug in Phase 2a study for hypercholesterolemia, markedly reduces hepatic lipid accumulation and alleviates MASH in two different mouse models of MASH. Mechanistic studies demonstrated that 326E exerts these effects not only by inhibiting ATP-citrate lyase (ACLY) to reduce de novo lipogenesis but also as a PPARα agonist to increase hepatic fatty acid oxidation with promoted mitochondrial biogenesis. Subsequent studies in cynomolgus monkeys (Macaca fascicularis) confirmed the effectiveness of 326E for MASH in primate species. In a randomized Phase 1b/2a clinical trial in MASH patients 326E was well tolerated and demonstrated a therapeutic potential for MASH signatures. Our results reveal a promising therapeutic potential of 326E for MASH via distinctive dual mechanisms of inhibiting ACLY while activating PPARα.
2025-10-17 | GSE279675 | GEO
Project description:Metabolic dysfunction–associated steatohepatitis (MASH) is a rapidly growing cause of hepatocellular carcinoma (HCC) and is associated with poor clinical outcomes and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that immune dysregulation within the tumor microenvironment contributes to disease progression; however, the transcriptional programs distinguishing MASH-associated HCC from non-MASH HCC remain incompletely characterized. To address this gap, we performed bulk RNA sequencing on total RNA isolated from MASH and non-MASH tumor tissues. This dataset was generated to enable comparative transcriptomic analysis of tumor-intrinsic and immune-related pathways associated with MASH-driven hepatocarcinogenesis, with particular relevance to immune organization, metabolic stress responses, and tumor–immune interactions.The resulting RNA-seq data provide a resource for investigating alterations in immune cell–associated gene signatures, metabolic pathways, and microenvironmental features that may underlie immune dysfunction in MASH-HCC.
2026-02-11 | GSE318726 | GEO
Project description:Metabolic dysfunction–associated steatohepatitis (MASH) is a rapidly growing cause of hepatocellular carcinoma (HCC) and is associated with poor clinical outcomes and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that immune dysregulation within the tumor microenvironment contributes to disease progression; however, the transcriptional programs distinguishing MASH-associated HCC from non-MASH HCC remain incompletely characterized. To address this gap, we performed bulk RNA sequencing on total RNA isolated from MASH and non-MASH tumor tissues. This dataset was generated to enable comparative transcriptomic analysis of tumor-intrinsic and immune-related pathways associated with MASH-driven hepatocarcinogenesis, with particular relevance to immune organization, metabolic stress responses, and tumor–immune interactions.The resulting RNA-seq data provide a resource for investigating alterations in immune cell–associated gene signatures, metabolic pathways, and microenvironmental features that may underlie immune dysfunction in MASH-HCC.
2026-02-11 | GSE318724 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) development is accompanied by the accumulation of immune cells within the hepatic microenvironment, yet its immunological networks remain obscure. Herein, we illustrate the profound reprogramming of the liver immune microenvironment during the transition from MASH to HCC by single-cell RNA sequencing (scRNA-seq).
2025-06-18 | GSE282630 | GEO