Targeting PSMD14 combined with arachidonic acid induces synthetic lethality via FADS1 m ⁶ A modification in triple-negative breast cancer

Dysregulation of deubiquitination is essential for cancer growth. However, the role of 26<i>S</i> proteasome non-ATPase regulatory subunit 14 (PSMD14) in the progression of triple-negative breast cancer (TNBC) remains to be determined. Gain- and loss-of-function experiments showed that silencing PSMD14 notably attenuated the growth, invasion, and metastasis of TNBC cells in vitro and in vivo. Overexpression of PSMD14 produced the opposite results. Mechanistically, PSMD14 decreased K63-linked ubiquitination on SF3B4 protein to de-ubiquitin and stabilize SF3B4 protein. Then, SF3B4/HNRNPC complex bound to FADS1 mRNA and promoted exon inclusion in the target mRNA through m⁶A site on FADS1 mRNA recognized by HNRNPC, thereby up-regulating the expression of FADS1 and activating Akt/mTOR signaling. Exogenous arachidonic acid supplementation combined with PSMD14 knockdown induced synthetic lethality, which was further confirmed in TNBC organoid (PDO) and TNBC patient-derived xenograft (PDX) mouse models. Overall, our findings reveal an oncogenic role of PSMD14 in TNBC progression, which indicates a potential biomarker and ferroptosis-mediated therapeutic strategy for TNBC.