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Inhibition of ACLY enhances tumor immunogenicity and resolves MASH-driven HCC

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE297081 | GEO | 2025/06/30

REPOSITORIES: GEO

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Inhibition of ACLY enhances tumor immunogenicity and resolves MASH-driven HCC [scRNA-seq]

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

Inhibition of ACLY enhances tumor immunogenicity and resolves MASH-driven HCC

2025-09-17 | GSE296668 | GEO

Inhibition of Acetyl-CoA metabolic enzymes by EVT0185 impairs hepatic stellate cell activation and reverses MASH and fibrosis in mouse models.

Project description:Metabolic Dysfunction-Associated Steatohepatitis (MASH) is characterized by liver steatosis and inflammation which lead to fibrosis following hepatic stellate cell (HSC) activation. Acetyl-CoA is fundamental for de novo lipogenesis (DNL) and cholesterol synthesis and can be derived from citrate via ATP citrate lyase (ACLY), or from acetate via acetyl-CoA synthetase (ACSS2). Here, we find that EVT0185, an ACLY and ACSS2 inhibitor, leads to resolution of MASH and fibrosis while lowering insulin and glucose in four distinct mouse models. EVT0185 also reduces fibrosis alone and in combination with semaglutide and more effectively than bempedoic acid in a model not characterized by steatosis or insulin resistance. Spatial transcriptomic and scRNAseq reveal marked downregulation of cholesterol synthesis in HSCs with EVT0185 treatment in vivo and in vitro. These data indicate a critical role for ACLY and ACSS2 in HSCs and suggest further clinical evaluation of EVT0185 for reducing MASH and fibrosis may be warranted.

2025-11-17 | GSE307420 | GEO

Inhibition of Acetyl-CoA metabolic enzymes by EVT0185 impairs hepatic stellate cell activation and reverses MASH and fibrosis in mouse models [nanostring]

2025-11-18 | GSE310332 | GEO

Spatial transcriptomic profiling of gene expression alterations following ACBP/DBI inhibition in a MASH-Driven HCC mouse model

Project description:We identified ACBP/DBI as a critical regulator in the pathogenesis of hepatocellular carcinoma (HCC), with its inhibition significantly impairing hepatocarcinogenesis in MASH-driven HCC models. To further elucidate the underlying transcriptional mechanisms, we performed spatial transcriptomic analyses using formalin-fixed, paraffin-embedded (FFPE) liver tissues from the following two experimental models: (i) Western diet (WD) and CCl₄-treated mice with tamoxifen-inducible ACBP/DBI knockout (Dbi⁻/⁻ mice), with Dbi⁺/⁺ littermates serving as controls, after a total of 27 weeks; (ii) WD and CCl₄-treated mice immunized with either keyhole limpet hemocyanin (KLH) alone or KLH-ACBP conjugate, after a total of 34 weeks.

2025-07-18 | GSE296545 | GEO

Hepatic ACLY deficiency and bempedoic acid drive divergent responses to dietary lipid

Project description:ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in non-alcoholic fatty liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol lowering drug bempedoic acid (BPA), which has been shown to improve steatosis in mice. However, the acetyl-CoA synthetase ACSS2 can compensate for ACLY deficiency to support DNL, potentially complicating the targeting of ACLY. We show that hepatic loss of both ACLY and ACSS2 reduces DNL. Nevertheless, even when ACSS2 is suppressed by dietary or genetic means, we find that steatosis is counterintuitively exacerbated with hepatic ACLY deficiency in mice fed a Western diet (WD), linked to reduced expression of PPARa target genes controlling fatty acid oxidation. Conversely, BPA treatment increased fat catabolism and ameliorated WD-mediated lipid accumulation in both WT and liver ACLY knockout mice. Thus, hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation, and BPA improves steatosis independent of ACLY.

2024-08-01 | GSE247358 | GEO

The enedioic acid analogue 326E alleviates MASH in preclinical studies and its signatures in patients via dual targeting at ACLY and PPARα [RNA-Seq]

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

The enedioic acid analogue 326E alleviates MASH in preclinical studies and its signatures in patients via dual targeting at ACLY and PPARα [ATAC-seq]

2025-10-17 | GSE279673 | GEO

Charaterization of potential roles and mechanisms of ACBP/DBI in NASH/MASH-dirven HCC mouse models

Project description:We demonstrated that ACBP/DBI inhibition impaired hepatocarcinogenesis in NASH/MASH-driven HCC models. To further investigate its potential mechanisms at transcriptional level in NASH/MASH-driven HCC models, we performed Bulk RNA-seq analyses with liver tissues from the following three models, namely, (i) WD/CCl4 with tamoxifen inducible ACBP/DBI knout mice (Dbi-/- mice, Dbi+/+ mice as control) for in total 27 weeks; (ii) WD/CCl4 with KLH/KLH-ACBP immunized mice for in total 34 weeks; and (iii) HFD/DEN with KLH/KLH-ACBP immunized miceI for a total of 36 weeks.

2025-04-18 | GSE255799 | GEO

Attenuation of early atherogenesis in LDLR-KO mice by proteasome inhibition

Project description:To get further insights into the processes leading to attenuation of early stage atherosclerosis in the bortezomib treated LDLR-KO mice, microarray profiling of gene expression was performed on RNA taken from whole aortae of bortezomib treated LDLR-KO and sham- treated LDLR-KO mice fed a Western diet for 6 weeks and compared the changes in gene expression in both groups to non-atherosclerotic CD animals. Male 10-week-old LDLR-KO mice (B6.129S7-Ldlrtm1Her/J; JAX Mice, Boston) were fed a Western-type diet for 6 weeks ad libitum and received intraperitoneal injections of bortezomib (50 µg/kg body weight; WD+Bor) or saline (WD) twice weekly (n = 4). Mice that were fed normal diet served as chow diet control (CD; n = 4). Gene expression in aortic tissue was measured. Two independent experiments were performed.

2011-07-13 | E-GEOD-30638 | biostudies-arrayexpress

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