Rewired DEPTOR-mTORC1/2 signaling stabilizes cardiac fibroblast survival and activation

Cardiac fibroblasts (CFs) are resistant to stress-induced death, a property important for tissue repair but also central to pathological fibrosis and heart failure. Comparative transcriptomic and proteomic analyses identified the mTOR-interacting protein DEPTOR as selectively enriched in CFs. Although DEPTOR is widely characterized as an inhibitor of mTORC1 and mTORC2 in tumor and immortalized cells, its role in differentiated somatic cells remains unclear. Here, we show that CFs display a context-dependent DEPTOR-mTOR signaling configuration in which DEPTOR sustains, rather than inhibits, mTOR-dependent outputs. DEPTOR silencing in adult CFs attenuates mTORC1 signaling with branch-specific sensitivity and strongly reduces BCL2, an integrative survival output of mTORC1/2 signaling. This leads to impaired α-smooth muscle actin induction and reduced fibroblast survival under stress, while AKT Ser473 phosphorylation remains comparatively buffered. Pharmacological dissection of the PI3K-mTOR axis supports DEPTOR as a stabilizer of this pro-survival network. Importantly, fibroblast-specific DEPTOR knockdown in vivo limits post-infarction fibrosis and preserves cardiac function. These findings redefine DEPTOR function in a differentiated somatic cell type, revealing a context-dependent mode of mTOR regulation shaping fibroblast behavior during cardiac injury.