Exploring Erdr1-Mid1 Axis: Shared Risk Factors and Molecular Mechanisms in Aging and Degenerative Diseases

Aging and degenerative diseases are characterized by the progressive decline in cellular, tissue, and organ function, resulting in a significant reduction in quality of life and posing major medical challenges. This highlights the urgent need to elucidate the underlying mechanisms and to develop innovative therapeutic approaches. In this study, we identify Erdr1 and Mid1 as shared risk factors for aging and multiple degenerative diseases. We propose that they contribute to disease progression by modulating oxidative stress, a well-established driver of aging and degenerative processes. We demonstrate that Erdr1 and Mid1 are both involved in oxidative stress regulation. Notably, Erdr1 undergoes alternative splicing in response to oxidative stress, resulting in reduced production of its antioxidant isoforms (Erdr1-177 and Erdr1-209), while promoting the secretion of its pro-oxidant isoform (Erdr1-145). Moreover, Erdr1-145 exacerbates oxidative damage by activating Mid1, a key inducer of oxidative stress. The Erdr1-Mid1-oxidative stress axis provides a molecular mechanistic basis for their shared role as risk factors for aging and degenerative diseases. Furthermore, we propose therapeutic strategies to mitigate cellular damage by regulating Erdr1 levels, implying a straightforward and effective approach for in situ repair of damage associated with aging and degenerative diseases. HighlightsO_LIErdr1 and Mid1 are shared risk factors in aging and multiple degenerative diseases. C_LIO_LIErdr1 and Mid1 contribute to cellular damage and degeneration by modulating oxidative stress. C_LIO_LIErdr1 undergoes alternative splicing in response to oxidative stress, downregulating antioxidant isoforms (Erdr1-177 and 209) while promoting the secretion of prooxidant isoform (Erdr1-145). C_LIO_LIErdr1-145 robustly primes oxidative stress by promoting Mid1 activation, thereby highlighting the role of the Erdr1-Mid1-oxidative stress axis in cellular damage. C_LIO_LIModulating Erdr1 indicates promising strategies for in situ repair of damage associated with aging and degenerative diseases. C_LI