The international journal of biochemistry & cell biology · 2026
ACSL1 suppresses breast cancer progression by activating ASK1/JNK pathway-mediated autophagy-dependent ferroptosis.
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Lin Luoqiang, Yang Yupeng, Zhang Zhenlong, Chen Xihai
Аннотация
BACKGROUND: ACSL1, a critical enzyme involved in fatty acid activation and oxidation, has been associated with several malignancies; however, its specific function in breast cancer remains a subject of debate.
OBJECTIVE: We sought to identify how ACSL1 operates biologically in breast cancer and to elucidate its modulatory effects on autophagy and ferroptosis.
METHODS: Analysis of ACSL1 expression in breast cancer was conducted using RNA sequencing, bioinformatics tools (GEPIA), and western blotting. In vitro experiments were carried out using MCF-7 and CAL-51 cells overexpressing ACSL1, either alone or following exposure to the autophagy inhibitor (3-Methyladenine, 3-MA) or ASK1/JNK cascade (GS-4997). Autophagic activity was assessed by visualizing LC3 puncta via immunofluorescence. Ferroptosis was evaluated by measuring intracellular Fe2 + levels with a commercial kit, and oxidative breakdown of lipids was analyzed by C11-BODIPY-based fluorescence detection in conjunction with corresponding assay kits. In vivo, a xenograft model of breast cancer was employed to assess tumor growth, histopathological changes, and ASK1/JNK pathway activation.
RESULTS: Decreased levels of ACSL1 were observed in breast cancer tissues. Ectopic expression of ACSL1 enhanced autophagic activity and triggered ferroptosis. Mechanistically, ACSL1 was found to activate the ASK1/JNK signaling axis, and pharmacological inhibition with GS-4997 abolished ACSL1-induced autophagy and ferroptosis. In vivo, overexpression of ACSL1 reduced tumor growth, suppressed proliferation, increased apoptosis, and enhanced autophagic activity, iron accumulation, and ASK1/JNK activation.
CONCLUSIONS: By activating ASK1/JNK pathway-driven, autophagy-dependent ferroptosis, ACSL1 exerts a tumor-suppressive role in breast cancer, underscoring its promise as a therapeutic target.
OBJECTIVE: We sought to identify how ACSL1 operates biologically in breast cancer and to elucidate its modulatory effects on autophagy and ferroptosis.
METHODS: Analysis of ACSL1 expression in breast cancer was conducted using RNA sequencing, bioinformatics tools (GEPIA), and western blotting. In vitro experiments were carried out using MCF-7 and CAL-51 cells overexpressing ACSL1, either alone or following exposure to the autophagy inhibitor (3-Methyladenine, 3-MA) or ASK1/JNK cascade (GS-4997). Autophagic activity was assessed by visualizing LC3 puncta via immunofluorescence. Ferroptosis was evaluated by measuring intracellular Fe2 + levels with a commercial kit, and oxidative breakdown of lipids was analyzed by C11-BODIPY-based fluorescence detection in conjunction with corresponding assay kits. In vivo, a xenograft model of breast cancer was employed to assess tumor growth, histopathological changes, and ASK1/JNK pathway activation.
RESULTS: Decreased levels of ACSL1 were observed in breast cancer tissues. Ectopic expression of ACSL1 enhanced autophagic activity and triggered ferroptosis. Mechanistically, ACSL1 was found to activate the ASK1/JNK signaling axis, and pharmacological inhibition with GS-4997 abolished ACSL1-induced autophagy and ferroptosis. In vivo, overexpression of ACSL1 reduced tumor growth, suppressed proliferation, increased apoptosis, and enhanced autophagic activity, iron accumulation, and ASK1/JNK activation.
CONCLUSIONS: By activating ASK1/JNK pathway-driven, autophagy-dependent ferroptosis, ACSL1 exerts a tumor-suppressive role in breast cancer, underscoring its promise as a therapeutic target.