The ABHD10-ACSL4 axis promotes pancreatic ductal adenocarcinoma growth via suppressing ferroptosis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis and limited treatment options. Ferroptosis has emerged as a potential therapeutic vulnerability in PDAC, but the upstream mechanisms regulating this process remain unclear. This study aimed to identify compounds with therapeutic potential against PDAC, determine their molecular targets, and elucidate how alpha/beta hydrolase domain-containing protein 10 (ABHD10) regulates tumor growth. A high-throughput compound screen against PDAC cell proliferation was performed, followed by limited proteolysis–mass spectrometry to identify the molecular target of halofuginone (HF). Target engagement was validated by surface plasmon resonance, cellular thermal shift assay, and drug affinity responsive target stability assay. Gain- and loss-of-function studies were conducted in PDAC cell lines and xenograft mouse models. Protein interaction, palmitoylation, and ferroptosis-related changes were evaluated using co-immunoprecipitation, acyl-biotinyl exchange, Click-iT labeling, transmission electron microscopy, and biochemical assays. Statistical analyses included Student’s t tests and one-way or two-way analysis of variance, as appropriate. HF significantly suppressed PDAC growth in vitro and in vivo. ABHD10 was identified as a direct binding target of HF and was upregulated in pancreatic cancer tissues and cell lines. Functional studies showed that ABHD10 promoted cell proliferation, survival, and tumor progression. Mechanistically, ABHD10 interacted with acyl-CoA synthetase long-chain family member 4 (ACSL4) and depalmitoylated it at cysteine 157, thereby suppressing ferroptosis. HF treatment or ABHD10 depletion increased ACSL4 palmitoylation, enhanced lipid peroxidation, disrupted redox homeostasis, and induced ferroptotic changes. Depletion of ACSL4 partially reversed these effects. The ABHD10–ACSL4 axis promotes PDAC growth by suppressing ferroptosis. Targeting this pathway may represent a promising therapeutic strategy for PDAC.