The right time, the right cell: the potential for precision senotherapy in pulmonary arterial hypertension.

Abstract

Pulmonary arterial hypertension (PAH) is a fatal vasculopathy driven by proinflammatory signaling that leads to pulmonary vascular remodeling and ultimately, right ventricular failure. Existing therapies fail to eliminate dysfunctional cells or reverse pathologic remodeling. Cellular senescence, a state of persistent cell-cycle arrest coupled with proinflammatory signaling, has emerged as a compelling, yet complex, contributor to PAH pathophysiology. Human data indicate that senescent cells accumulate within remodeled pulmonary vascular lesions and may promote proliferation and apoptosis resistance in neighboring cells. However, preclinical studies testing senolytic therapies in PAH have yielded conflicting results, raising uncertainty about their translational potential. This review will synthesize the current literature regarding cellular senescence in PAH and propose that heterogeneity in 1) senescent cell type, 2) senolytic mechanisms and off-target susceptibility, and 3) the disease stage at the time of intervention can help explain divergent outcomes. By addressing these three key points, this review will identify practical considerations for advancing "precision senotherapy" in PAH, including dosing strategies favoring intermittent, short-course senolytic regimens, and combination treatment approaches. Together, these concepts provide a framework for designing safer, stage-aware, cell-informed senotherapeutic studies in PAH.