Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons

Abstract

Cellular senescence, a state of permanent cell cycle arrest, represents a double-edged sword in biology-providing tumor-suppressive functions while contributing to tissue degeneration, chronic inflammation, and age-related diseases when senescent cells persist. A key driver of senescence is oxidative stress, primarily mediated by excessive reactive oxygen species that damage mitochondrial DNA, modulate redox-sensitive signaling pathways, and trigger the senescence-associated secretory phenotype. Emerging evidence highlights the pathogenic role of SASP in promoting local inflammation, immune evasion, and senescence propagation. This review explores the intricate interplay between redox imbalance and cellular senescence, emphasizing mitochondrial dysfunction, SASP dynamics, and their implications in aging and cancer. We discuss current senotherapeutic strategies-including senolytics, senomorphics, antioxidants, gene therapy, and immunotherapy-that aim to eliminate or modulate senescent cells to restore tissue homeostasis. Understanding the heterogeneity and context-specific behavior of senescent cells remains crucial for optimizing these therapies. Future research should focus on addressing key knowledge gaps, including the standardization of senescence biomarkers such as circulating miRNAs, refinement of predictive preclinical models, and development of composite clinical endpoints. These efforts are essential to translate mechanistic insights into effective senotherapeutic interventions and enable the safe integration of senescence-targeting strategies into routine clinical practice.

Keywords: DNA damage response; Nrf2 pathway; SASP; aging; cancer; cellular senescence; mitochondrial dysfunction; oxidativestress; redox signaling; senotherapy.

Figure 1

Senescent cell and SASP-mediated effects on tissue and tumor biology. Senescent cells, despite their proliferative arrest, remain metabolically active and secrete an array of bioactive factors collectively termed the senescence-associated secretory phenotype (SASP). SASP factors are transcriptionally regulated predominantly by NF-κB and contribute to a broad spectrum of physiological and pathological outcomes. The figure illustrates how SASP factors influence the following: (1) induction and maintenance of cell cycle arrest; (2) recruitment of immune cells (e.g., NK cells, T cells, macrophages), facilitating immune clearance of tumor cells; (3) promotion of angiogenesis, supporting tumor vascularization; (4) enhancement of metastatic dissemination of tumor cells; (5) immune evasion via mechanisms such as PD-1/PD-L1 axis activation and recruitment of myeloid-derived suppressor cells (MDSCs). This pleiotropic activity underscores the dualistic nature of senescence in health and disease, balancing regenerative processes with the risk of chronic inflammation and malignancy progression.

Figure 2

Mechanistic pathways linking oxidative stress to cellular senescence and SASP activation. Oxidative stress induces cellular senescence primarily through DNA damage response (DDR) activation, leading to a cascade of molecular events that enforce cell cycle arrest. The central DDR machinery involves the ATM/checkpoint kinase 2 (CHK2)/p53/p21 axis and the Rad3-related (ATR)/checkpoint kinase 1 (CHK1)/mitogen-activated protein kinase kinase 3 (MKK3)–p38/p16 pathway. These converging routes inhibit cyclin-dependent kinases (CDK1, CDK2, CDK4, CDK6) and cyclins (A, E, D), ultimately suppressing phosphorylation of the retinoblastoma protein (pRB) and halting cell cycle progression. This checkpoint blockade ensures a stable senescent phenotype characterized by resistance to apoptosis, cellular enlargement, morphological changes, and flattened cell shape. Additionally, senescent cells exhibit increased senescence-associated β-galactosidase (SA-β-GAL) activity and heightened mitochondrial ROS (↑ROS) production, which further amplifies redox imbalance. NF-κB activation drives the transcription of SASP genes, culminating in the secretion of diverse inflammatory and tissue-remodeling factors. These SASP components perpetuate senescence in an autocrine manner and propagate paracrine senescence in surrounding cells, thereby contributing to tissue dysfunction, chronic inflammation, and tumorigenic processes.