The simultaneous targeted Inhibition of ISG15 and HMGCR disrupts cancer stemness through metabolic collapse and induces synthetic lethality in pancreatic ductal adenocarcinoma.

[UNLABELLED] Precision oncology, a transformative paradigm in cancer therapeutics, leverages molecular profiling to design personalized interventions. Building on our prior discovery of ISG15’s role in pancreatic cancer stem cell (CSC) generation, we identified co-upregulation of ISG15 and HMGCR in pancreatic ductal adenocarcinoma (PDAC). Dual suppression of ISG15 and HMGCR triggered synthetic lethality, effectively eradicating CSCs and impairing tumor progression. To exploit this synergy, we engineered a hyaluronic acid-coated liposomal nanoplatform (LNP-Kd/Statin) for co-delivery of ISG15-targeting siRNA and HMGCR-inhibiting statins. Mechanistically, ISG15 directly interacts with HMGCR, and the knockdown of ISG15 stabilizes the HMGCR protein by inhibiting K48 ubiquitin-proteasomal degradation, a process that occurs independently of ISGylation, paradoxically elevating cholesterol levels to sustain cell survival while depleting metabolic intermediates, thereby inducing vulnerability. Sterolomics profiling confirmed this metabolic rewiring, linking cholesterol flux collapse to CSC elimination. Our findings not only elucidate a novel ISG15-HMGCR regulatory axis in PDAC pathogenesis but also establish a nanotechnology-enabled strategy to disrupt cancer stemness through metabolic targeting. This work advances the translational potential of synthetic lethality in precision oncology for aggressive malignancies.

[GRAPHICAL ABSTRACT] [Image: see text]

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s13046-025-03561-x.