JWA as a context-dependent redox regulatory hub linking stress responses with aging hallmarks and age-related diseases

JWA (also known as ARL6IP5) is an evolutionarily conserved multifunctional protein increasingly implicated in redox homeostasis and cellular stress adaptation. Its functions intersect with redox homeostasis through signaling pathways including mitogen-activated protein kinase (MAPK), nuclear factor-erythroid 2-related factor 2 (Nrf2), and adenosine 5′-monophosphate-activated protein kinase (AMPK), as well as interactions with key proteins such as X-ray repair cross-complementing 1 (XRCC1), nuclear receptor coactivator 4 (NCOA4), and excitatory amino acid carrier 1 (EAAC1) involved in oxidative-stress adaptation. As a redox-responsive regulatory protein and mediator, JWA exhibits context-dependent roles in disease pathogenesis: in oncology, it acts as a tumor suppressor by mitigating oxidative stress-induced DNA damage and reversing chemoresistance, with reduced expression correlating with poor prognosis in gastric cancer, hepatocellular carcinoma, and other malignancies; in neurobiology, it exerts neuroprotective effects through suppression of ferroptosis, regulation of glutamate homeostasis, and proteostasis-related mechanisms, with the strength and direction of redox involvement varying across experimental contexts; beyond these fields, JWA regulates intestinal barrier integrity, radiation response, and adaptation to environmental oxidants (Cd, B [a]P, H 2 O 2 ), while specific polymorphisms influence redox-related disease susceptibility. As a potential aging-associated regulator, accumulating evidence suggests that JWA expression or activity may change during aging, although age-, tissue-, and disease-specific patterns remain incompletely defined. Current evidence links JWA dysregulation to oxidative stress and tissue dysfunction in several age-associated diseases, whereas its direct roles in the aging process remain insufficiently established. This review, centered on redox regulation as the unifying framework, comprehensively synthesizes current knowledge on JWA’s multifunctional roles across disciplines, highlights its potential as a candidate redox-related biomarker and experimental therapeutic target, and proposes an evidence-based research framework for future investigation and translation. By emphasizing JWA’s role in maintaining redox balance and its regulatory function in aging process and age-related diseases, we provide novel insights into its significance in future clinical-development considerations and offer directions for targeting redox dysregulation in refractory diseases.