Pelvic organ prolapse: emerging concepts in molecular mechanisms and tissue repair

Pelvic organ prolapse (POP) is a common and progressive pelvic floor disorder associated with pregnancy and vaginal delivery, ageing, obesity, menopause and other conditions that increase or prolong mechanical burden on pelvic supportive tissues. Previous studies have linked POP to extracellular matrix remodeling, oxidative stress, hormonal changes, genetic susceptibility and fibroblast dysfunction. However, these findings are still often presented as separate pathogenic theories or molecular observations, which makes it difficult to explain how mechanical challenge, cellular dysfunction and structural failure are biologically connected during disease progression. In this Review, we propose that POP can be more coherently understood along a mechanics–cell–matrix axis. Within this framework, chronic mechanical loading and impaired adaptive repair are regarded as the disease-setting in which prolapse develops. Mechanotransduction-related pathways are then considered the upstream bridge linking altered tissue mechanics to fibroblast state change. Oxidative stress, autophagy-related disturbance, apoptosis and senescence are further discussed as bridge-amplifier processes that deepen repair failure, whereas extracellular matrix imbalance is viewed as the structural endpoint of declining tissue support. Hormonal status, genetic susceptibility and immune remodeling further influence the course of POP. Fibrosis-associated fibroblast activation may coexist with collagen disorganization, matrix degradation and impaired elastic recoil. This review connects these tissue findings with the distinctive mechanical demands of pelvic support and considers their implications for repair (Tian et al., BJOG, 2024, 131, 1029–1041; Guler and Roovers, Biomolecules, 2022, 12, 94; Wu et al., Front. Med., 2024, 11, 1303044; Ruiz-Zapata et al., Sci. Rep., 2016, 6, 22971).