Fig. 2: Mechanistic overview of therapy-induced senescence (TIS) vulnerabilities and senolytic action of dmXeB.

Schematic representation illustrating the interplay between mitochondria and the endoplasmic reticulum (ER) in TIS cells. Therapy-induced senescence, triggered by chemotherapeutic agents such as Doxorubicin and Etoposide, leads to an increase in mitochondria-ER contact sites (MERCS) but a reduction in ER-to-mitochondria Ca²⁺ flux. This is associated with decreased expression of IP3R isoforms and disrupted IP3R1-VDAC interactions, impairing Ca²⁺ transfer while preserving MERCS integrity. dmXeB, an IP3R inhibitor, selectively targets TIS cells by further inhibiting ER-mitochondria Ca²⁺ flux, inducing apoptotic-like cell death via mechanisms partially dependent on necroptosis and caspase pathways. In vivo, dmXeB effectively reduces senescent cell burden in aged p16-3MR transgenic mice, as evidenced by decreased p16 fluorescence in liver tissue and reduced SA-β-galactosidase staining in subcutaneous fat. This figure highlights a novel therapeutic strategy targeting Ca²⁺ signaling vulnerabilities in senescent cells.