Targeting Ferroptosis to Eliminate Senescent Cells: Mechanisms and Therapeutic Potential.

Abstract

Cellular senescence is involved in early development, wound healing, and tumor suppression. However, the accumulation of senescent cells (SCs) drives tissue dysfunction and many age associated pathologies such as cancer and neurodegeneration. SCs demonstrate irreversible cessation of cell cycle, overexpression of anti-apodotic proteins, and senescence associated secretory phenotype (SASP), cause tissue dysfunction. Traditional senolytics induces apoptosis but have poor selectivity, uncertain long-term efficacy, and resistant SCs, limiting their use. Ferroptosis, an iron-dependent, non-apoptotic form of programmed cell death, has emerged as a promising alternative. SCs bypass the apoptosis by overexpression of an anti-apoptotic pathway, but ferroptosis uses oxidative damage to overcome these defenses, thus, making it effective for eliminating SCs. This review critically evaluates ferroptosis-mediated processes such as elevated level of iron, polyunsaturated fatty acids (PUFAs) and oxidative damages in elimination of SCs and its therapeutic potential for age related pathologies including fibrosis, cancer and neurodegenerative diseases. This review highlights the molecular mechanisms underlying ferroptosis and its potential for treating age-related diseases such as fibrosis, atherosclerosis, osteoarthritis, and neurodegeneration. By addressing the translational challenges of ferroptosis-based therapies, we emphasize its potential as a next generation senolytic for targeting senescence and aging-related pathologies.