Senescent progenitor cells in the distal lung and major respiratory diseases: underlying mechanisms and therapeutic strategies

Abstract Driven by the accelerating global aging trend, age-related respiratory diseases are becoming increasingly prevalent, severely compromising quality of life and imposing substantial socioeconomic burdens. A key underlying mechanism involves the senescence of pulmonary progenitor cells. The distal airways and alveoli harbor a diverse array of cell types that, upon injury, can function as progenitors—migrating to damaged sites and contributing to lung regeneration. However, disease-associated pathological processes can induce senescence in these cells, impairing their differentiation capacity, perturbing signaling pathways, and exerting detrimental paracrine effects—thereby significantly driving disease progression. Moreover, immune dysregulation further exacerbates this pathological cascade. Accumulating evidence highlights the therapeutic potential of targeting senescent pulmonary progenitors in major respiratory diseases, with strategies including senotherapy, activation of endogenous progenitors, and exogenous progenitor transplantation. Consequently, elucidating the interplay between progenitor senescence and respiratory disease pathogenesis not only deepens our mechanistic understanding but also establishes a foundation for developing novel, senescence-targeted therapies that hold promise for clinical translation.