A novel Skp2 inhibitor triggers pyroptosis in leukemia via phospholipid metabolism disorder and mitochondria-associated endoplasmic reticulum membranes.

Authors

Xiaolong Tian, Jiarun Li, Guancui Yang, Peijie Jiang, Xueqing Yang, Shijie Yang, Xi Zhang, Jinyi Liu

Published in

Archives of pharmacal research. Aug 24, 2026. Epub Aug 24, 2026.

Abstract

Philadelphia chromosome-positive (Ph⁺) leukemia is among the most aggressive forms of leukemia and arises from the Philadelphia chromosome (Bcr-Abl fusion gene) abnormality. This disease is associated with a poor prognosis in adults and resistance to traditional treatment. Thus, the identification of novel therapeutic targets and drugs for Ph⁺ leukemia remains crucial. S-phase kinase-associated protein 2 (Skp2), a key component of the SCF ubiquitin ligase complex, is aberrantly overexpressed in various malignancies and therefore represents a potential target for anticancer therapy. This study aimed to elucidate the therapeutic mechanism of action of AAA-237, a novel Skp2 inhibitor, in Ph + leukaemia. Cellular responses to AAA-237 were evaluated using cell viability, EdU incorporation, and colony formation assays. Pyroptosis was observed by scanning electron microscopy (SEM), immunofluorescence, lactate dehydrogenase (LDH) detection, ELISA, and Western blotting. Phospholipid metabolism was evaluated through metabolomic profiling and RNA sequencing. Mechanistic findings were validated using Western blotting and quantitative real-time PCR. Mitochondrial and endoplasmic reticulum damage were evaluated using Ca²⁺, ATP, TMRM, and mitochondrial reactive oxygen species (ROS) assays. In vivo efficacy and safety of AAA-237 were examined in a xenograft model. The results showed that AAA-237 targeted Skp2 and inhibited Bcr-Abl phosphorylation and ubiquitination, suppressing the proliferation of Ph⁺ leukemia cells in a concentration-dependent manner at the cellular level. AAA-237 induced both pyroptosis and apoptosis through caspase-dependent mechanisms. Treatment with AAA-237 inhibited the PI3K/AKT signaling pathway and disrupted phospholipid metabolism, resulting in dysregulated phospholipid metabolism. AAA-237 also increased PACS2 expression, remodeled mitochondria-associated endoplasmic reticulum membranes (MAMs), and induced mitochondrial dysfunction and endoplasmic reticulum damage. In vivo, AAA-237 effectively suppressed leukemia progression. These results show that AAA-237, a novel Skp2 inhibitor, inhibits the proliferation of Ph⁺ leukemia cells by reducing Bcr-Abl phosphorylation and ubiquitination. AAA-237 further induces caspase-dependent pyroptosis and apoptosis by disrupting phospholipid metabolism and impairing MAM homeostasis. These results provide preliminary experimental evidence supporting the development of targeted candidate therapeutics for Ph⁺ leukemia.

PMID:
42635941
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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