ACAA1

ACAA1 is a peroxisomal thiolase that catalyzes the terminal cleavage of 3-ketoacyl-CoA into acetyl-CoA and acyl-CoA in peroxisomal fatty acid β-oxidation, positioning it as a control point for cellular lipid catabolism (PMID:34234807). Its expression is set transcriptionally by PPARα, whose repression by benzo[a]pyrene impairs peroxisomal fatty acid degradation and drives hepatic steatosis (PMID:41539557), and by ATF1, while oncogenic KRAS suppresses ACAA1 mRNA through MAPK signaling (PMID:33194642, PMID:42181662). Post-translationally, ACAA1 thiolase activity is inhibited by the molecular glue CLEO4-88, which binds the CTLH E3 ligase subunit GID4 and induces an allosteric conformational change promoting a GID4–ACAA1 ternary complex that blocks catalysis without driving ubiquitination (PMID:41957281). Through its catabolic activity ACAA1 acts as a negative regulator of adipocyte differentiation, with its loss increasing lipid accumulation and adipogenic transcription factors PPARγ and C/EBPα (PMID:34234807). Beyond lipid metabolism, ACAA1 has been linked to cancer cell biology: it physically interacts with CDK4 to support RB1 phosphorylation and G1-S progression (PMID:37129951), supplies substrate flux that sustains mitochondrial ATP production and mTOR activity in PDAC cells such that its loss induces autophagy and tumor growth arrest (PMID:40848971), and activates a PI3K/AKT/Nrf2 axis that suppresses ferroptosis (PMID:41052583, PMID:42181662). A missense variant, p.N299S, disrupts ACAA1 thiolase activity, impairs lysosomal function, and aggravates amyloid-β pathology and cognitive impairment in a murine model of early-onset Alzheimer's disease (PMID:34465723).

1. 2019 Medium

   Established a post-transcriptional control point for ACAA1, showing that miR-15a directly represses it to redirect fatty acid handling toward preadipocyte differentiation.

   Evidence Dual-luciferase 3'UTR reporter and miR-15a mimic transfection in chicken preadipocytes/DF1 cells

   PMID:31434294

   Open questions at the time

   • Performed in chicken cells; human relevance not tested
   • Link between reduced β-oxidation and adipogenesis is indirect
   • No measurement of thiolase activity itself
2. 2020 Medium

   Connected oncogenic signaling to ACAA1, showing that mutant KRAS suppresses ACAA1 mRNA via the MAPK pathway in lung cancer cells.

   Evidence siRNA knockdown of KRASG13D and sorafenib treatment with qPCR readout in H1944 NSCLC cells

   PMID:33194642

   Open questions at the time

   • Transcription factor mediating MAPK-dependent repression not identified
   • Functional consequence of ACAA1 loss in this context not measured
   • Single cell line
3. 2021 Medium

   Defined ACAA1's enzymatic role and its function as a negative regulator of adipocyte differentiation through bidirectional genetic manipulation.

   Evidence siRNA knockdown and overexpression in sheep preadipocytes with Oil Red O, triglyceride assay, and adipogenic marker qRT-PCR

   PMID:34234807

   Open questions at the time

   • Mechanistic link from β-oxidation flux to PPARγ/C/EBPα regulation not resolved
   • Performed in sheep cells
   • No direct enzymatic activity assay
4. 2021 High

   Linked ACAA1 enzymatic loss-of-function to disease, demonstrating a missense variant that abolishes thiolase activity and drives Alzheimer's pathology via lysosomal dysfunction.

   Evidence Whole-genome sequencing, in vitro enzymatic assays, and an in vivo mouse model with Aβ pathology and cognitive testing

   PMID:34465723

   Open questions at the time

   • Mechanism linking peroxisomal thiolase deficit to lysosomal dysfunction not fully defined
   • Single variant studied
   • Penetrance and human genetic spectrum not established
5. 2023 Medium

   Revealed a non-metabolic, cell-cycle role for ACAA1 through a physical interaction with CDK4 controlling RB1 phosphorylation.

   Evidence Co-IP, RB1 phosphorylation immunoblot, cell-cycle analysis, and ACAA1 inhibition in TNBC cells and mouse models

   PMID:37129951

   Open questions at the time

   • Co-IP without reciprocal validation or structural mapping of the interaction
   • Whether the interaction depends on thiolase activity unknown
   • Direct vs indirect CDK4 binding not resolved
6. 2025 High

   Established ACAA1 as a metabolic dependency in PDAC, showing its substrate flux sustains mitochondrial ATP and mTOR activity, with cancer-cell-specific loss inducing autophagy and growth arrest.

   Evidence Knockout/knockdown with Seahorse OCR, ATP measurement, LC3-II immunoblot, xenografts, and KPC mouse survival

   PMID:40848971

   Open questions at the time

   • Molecular basis of cancer-cell selectivity not defined
   • Mechanism by which a peroxisomal enzyme supplies mitochondrial substrate not fully mapped
7. 2025 Medium

   Identified a pro-tumor signaling output of ACAA1, showing it activates PI3K/AKT/Nrf2 to suppress ferroptosis in endometrial cancer.

   Evidence Overexpression in EC cell lines with pathway phosphorylation, Nrf2 translocation, ferroptosis assays, and xenografts

   PMID:41052583

   Open questions at the time

   • How a metabolic enzyme triggers PI3K/AKT activation is unresolved
   • Relies on overexpression
   • Direct vs indirect pathway engagement unclear
8. 2025 Medium

   Defined ATF1 as an upstream transcriptional activator of ACAA1 and showed ACAA1 limits arachidonic acid-driven membrane peroxidation independently of ACSL4.

   Evidence Overexpression in renal tubular epithelial cells with peroxidomics, phospholipid profiling, ferroptosis/crystal adhesion assays, and ATF1 rescue

   PMID:42181662

   Open questions at the time

   • Direct ATF1 binding to the ACAA1 promoter not demonstrated
   • Generality of the ACSL4-independent mechanism across tissues unknown
9. 2026 Medium

   Demonstrated PPARα-dependent transcriptional control of ACAA1 in vivo, showing benzo[a]pyrene represses PPARα/ACAA1 to cause hepatic steatosis.

   Evidence In vivo and in vitro BaP exposure with PPARα binding analysis, ACAA1 expression, and lipid accumulation assays plus network toxicology

   PMID:41539557

   Open questions at the time

   • Partly bioinformatic; direct PPARα occupancy at the ACAA1 locus not fully defined
   • Contribution of ACAA1 loss vs broader PPARα targets to steatosis not isolated
10. 2026 High

    Defined a pharmacological mechanism to silence ACAA1 enzymatic activity, showing a molecular glue acts through GID4 to allosterically inhibit thiolase activity without degradation.

    Evidence Biochemical ternary complex assay, cryo-EM/atomic structure, in vitro thiolase activity assay, and cellular target engagement

    PMID:41957281

    Open questions at the time

    • Therapeutic context and selectivity in disease models not established here
    • Whether GID4 has any endogenous role in regulating ACAA1 unknown

• How ACAA1's peroxisomal thiolase activity mechanistically connects to its reported non-catabolic functions (CDK4 binding, PI3K/AKT/Nrf2 activation, mitochondrial ATP supply) remains unresolved.
• No structural or genetic test of whether catalytic activity is required for the cell-cycle and signaling roles
• No unified model reconciling lipid catabolism with the cancer signaling outputs