Extracellular matrix dysregulation in aging, calcification, and cancer diseases: insights into cellular senescence, inflammation, and novel therapeutic strategies

This review underscores the dynamic role of the extracellular matrix (ECM) in regulating cellular behavior and maintaining tissue homeostasis, highlighting its pivotal involvement in aging, calcification, and cancer diseases. In healthy tissues, controlled ECM remodeling provides essential biochemical and mechanical cues, but dysregulation (driven by chronic inflammation, cellular senescence, and altered intercellular communication) leads to fibrosis, calcification, and the creation of a pro-tumorigenic microenvironment. Senescent cells contribute to these changes through senescence-associated secretory phenotype (SASP), which reinforces inflammation and matrix degradation, while extracellular vesicles (EVs) mediate intercellular signaling and further modulate ECM structure and function. In cancer, ECM remodeling not only facilitates tumor progression and metastasis by forming physical and biochemical barriers but also hinders the efficacy of conventional and immunotherapeutic interventions. Similarly, in cardiovascular diseases, aberrant ECM remodeling exacerbates tissue damage and impairs regenerative processes. Emerging therapeutic strategies aim to restore ECM homeostasis through targeted interventions, including ECM-normalizing agents, EV-based therapies, and stem cell approaches that modulate matrix composition to improve tissue repair. By elucidating the complex interplay between ECM dysfunction, cellular senescence, and chronic inflammation, this review highlights promising avenues for developing personalized treatments that address the underlying causes of age-related and tumorigenic pathologies, ultimately, the way to improved clinical outcomes.