TSPYL5 desensitizes triple-negative breast cancer to paclitaxel via promoting PINK1-PRKN-mediated mitophagy

Acquired Paclitaxel (PTX) resistance leads to treatment failure and poor clinical prognosis in triple-negative breast cancer (TNBC). Accumulating evidence has demonstrated that aberrant mitophagy, a critical type of selective autophagy that maintains mitochondrial homeostasis, contributes to chemoresistance in multiple malignancies. Testis-specific Y-like protein 5 (TSPYL5) has been reported to induce drug resistance in several cancer types and acts as a core oncogenic driver and promotes invasion and metastasis in TNBC, but its roles in PTX-resistant TNBC remain unknown. Mitochondrial function, cell apoptosis and drug sensitivity were detected in the TNBC cells with gain- and loss-of-function of TSPYL5. Biochemical assays including Co-immunoprecipitation, Western blot and Cycloheximide chase were used to elucidate the molecular mechanism underlying TSPYL5-PINK1-PRKN-mediated mitophagy. Xenograft models and immunohistochemical examinations were utilized to evaluate the therapeutic effects of PTX and combined it with mitophagy inhibitor chloroquine. TSPYL5 increases the IC50 of PTX and enhances its resistance in TNBC cells through suppressing PTX-induced apoptosis. TSPYL5 augments mitophagy to maintain cellular homeostasis via PINK1-Parkin pathway, in which TSPYL5 interacts with PINK1 to restrain its ubiquitination and proteasomal degradation. And in vivo examinations further confirmed that mitophagy inhibition reverses TSPYL5-mediated PTX resistance in TNBC. Our findings reveal that TSPYL5-induced mitophagy contributes to TNBC progression and PTX resistance through the PINK1-Parkin signaling. This study expands our mechanistic understanding of mitophagy-driven chemoprotection and offers actionable molecular targets for combination therapy regimens in refractory TNBC.