CST1 Regulates ER-Mitochondrial Mg²⁺ Balance via MAGT1 to Promote Breast Cancer Metabolism and Growth.

Breast cancer remains a clinical challenge and requires novel molecular targets. Here, we identify the Cystatin SN (CST1) as a critical oncoprotein upregulated in breast cancer, where its expression correlates with poor prognosis. Functionally, CST1 promotes breast cancer cell proliferation and tumor growth in vitro and in vivo, independent of its secretion. Mechanistically, CST1 physically interacts with the magnesium transporter MAGT1 on the endoplasmic reticulum (ER) membrane, and this interaction potentiates MAGT1-mediated Mg²⁺ transport, elevating mitochondrial Mg²⁺ levels and fueling mitochondrial metabolism. We developed a cell-penetrating peptide TAT-TM42 which disrupts the CST1-MAGT1 interface and effectively suppresses Mg²⁺ flux, mitochondrial metabolism, and tumor growth in vivo. Our study unveils a non-canonical role for a secreted protein in regulating inter-organelle ion homeostasis to drive cancer metabolism and growth, and proposes a targeted peptide-based strategy for treating breast cancer.