PPT1 regulates mitochondrial redox by depalmitoylating PRDX3.

Multiple myeloma (MM) remains an incurable hematological cancer, with an enhanced antioxidant capacity that fuels disease progression. Peroxiredoxins (PRDXs), central players of redox homeostasis, are overexpressed in cancers including MM, and their high expression correlates with poor prognosis. However, the detailed mechanisms underlying how PRDXs are regulated in the context of redox homeostasis and MM pathogenesis remain unclear. In this study, we identify PPT1 as a promising therapeutic target that sustains PRDX3 antioxidant activity by catalyzing its depalmitoylation at the catalytic cysteine (C108). We demonstrated that genetic or chemical inhibition of PPT1 induced cytotoxicity in MM cells through a mechanism involving elevated mitochondrial reactive oxygen species (mtROS). Furthermore, PPT1 inhibition significantly suppressed the growth of xenograft tumors and increased the level of PRDX3 S-palmitoylation. Collectively, our study identifies PPT1 as the bona fide depalmitoylase of PRDX3 and establishes this axis as a promising therapeutic target in MM.