PhSAN induces PANoptosis via targeting RNF25-mediated endoplasmic reticulum stress.

PANoptosis is an inflammatory programmed cell death (PCD) pathway integrating pyroptosis, apoptosis, and necroptosis, typically triggered by extrinsic stressors such as pathogen-associated signals. However, whether tumor-intrinsic stress can activate PANoptosis and the underlying regulatory mechanisms remain unclear. Here, we show that sustained and unresolved endoplasmic reticulum (ER) stress induces PANoptosis in renal cell carcinoma (RCC). Mechanistically, inhibition of the E3 ubiquitin ligase RNF25 disrupts eEF1A ubiquitination and degradation, leading to its aberrant accumulation. This accumulation impairs proteostasis and provokes ER stress. When combined with thapsigargin (Tg), which further exacerbates ER stress beyond the adaptive threshold, this sustained and unresolved tumor-intrinsic stress signal triggers PANoptosis. We further identify 3-(phenylsulfonyl)acrylonitrile (PhSAN) as a selective inhibitor of RNF25 that suppresses its ubiquitin ligase activity and induces ER stress. Notably, the combination of PhSAN and bortezomib (BTZ) drives ER stress, synergistically activating PANoptosis and significantly inhibiting tumor growth in RCC. Our findings establish sustained and unresolved ER stress as a key upstream signal for PANoptosis induction and propose a novel therapeutic strategy for overcoming treatment resistance in RCC through pharmacological inhibition of RNF25 with PhSAN in combination with BTZ.