KRAS/ABHD17C/ALOX15B Axis Promotes Pancreatic Cancer Progression via Ferroptosis Evasion

Man Li; Xuexin Yu; Yuanji Liu; Shuqin Ouyang; Long Wu; Xiaohong Chen; Huiqi Yu; Haoming Chen; Senmao Lian; Ziwen Li; Liyun Gong; Libing Song; Jun Li

doi:10.1002/advs.202504470

KRAS/ABHD17C/ALOX15B Axis Promotes Pancreatic Cancer Progression via Ferroptosis Evasion

Adv Sci (Weinh). 2025 Jun 26:e04470. doi: 10.1002/advs.202504470. Online ahead of print.

Authors

Man Li^{1

2}, Xuexin Yu², Yuanji Liu², Shuqin Ouyang³, Long Wu⁴, Xiaohong Chen², Huiqi Yu², Haoming Chen⁴, Senmao Lian⁴, Ziwen Li², Liyun Gong⁵, Libing Song¹, Jun Li^{1

2}

Affiliations

¹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510080, China.
² Department of Biochemistry, Zhongshan School of Medicine Sun Yat-sen University, Guangzhou, 510080, China.
³ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510080, China.
⁴ Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
⁵ Guangdong Provincial Key Laboratory for Genome Stability and Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518061, China.

PMID: 40569151
DOI: 10.1002/advs.202504470

Abstract

Understanding the mechanisms underlying Kirsten rat sarcoma (KRAS) mutation-driven development and progression of pancreatic ductal adenocarcinoma (PDAC) may facilitate the discovery of novel strategies for KRAS-mutant PDAC (KRAS^mut-PDAC) treatment. Here, it is reported that downregulation of arachidonate 15-lipoxygenase (ALOX15B) significantly correlated with poor outcomes in patients with KRAS^mut-PDAC. Mechanistically, KRAS^mut/ERK1-elicited phosphorylation of ABHD17C promotes depalmitoylation and membrane-to-cytoplasm translocation of ALOX15B, facilitating proteasome-dependent degradation of ALOX15B via interaction with the E3 ligase complex CUL4/DDB1/DCAF10. Notably, treatment with methyl protodioscin (MPD), a steroid saponin primarily purified from polygonatum sibiricum rhizome, restored the S-palmitoylation and membrane location of ALOX15B via disruption of the ABHD17C/ALOX15B interaction, consequently resulting in significant inhibition of growth rate of patient-derived KRAS^mut-PDAC organoids in vitro and KRAS^mut-PDAC-formed tumor in vivo via induction of ferroptosis. Therefore, these findings unveil a prominent role of ferroptosis evasion in KRAS^mut-PDAC progression and highlight the potential of targeting KRAS/ERK1/ABHD17C/ALOX15B axis in KRAS^mut-PDAC treatment.

Keywords: ABHD17C; ALOX15B; KRAS mutation; ferroptosis; pancreatic ductal adenocarcinoma.

Abstract

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