International Immunopharmacology · Apr 19, 2025

Urolithin A alleviates radiation pneumonitis by activating PINK1/PRKN-mediated Mitophagy

By Zhang A, Luo S, Li P et al.

BACKGROUND: Radiation pneumonitis (RP) is a common and severe complication of radiotherapy, whose pathogenesis involves complex inflammatory responses and cellular damage. Despite its clinical significance, effective treatments remain limited. This study investigates the role of radiation-induced PINK1/PRKN-mediated mitophagy and type I interferon responses in RP and evaluates the therapeutic potential of Urolithin A (UA) in regulating inflammation through mitophagy activation. METHODS: We established RP mouse models (20 Gy thoracic irradiation) and radiation-induced BEAS-2B cell models (6 Gy). We systematically investigated mitochondrial damage, mtRNA release, RIG-I/MDA5-MAVS pathway activation, and PINK1/PRKN-mediated mitophagy changes. Moreover, the effects of UA and the mitophagy inhibitor Mdivi-1 on inflammation and lung injury were analyzed. RESULTS: Radiation significantly caused mitochondrial damage in lung tissues, inducing mtRNA release and RIG-I/MDA5-MAVS-mediated type I interferon response. PINK1/PRKN-mediated mitophagy was significantly enhanced, clearing damaged mitochondria and reducing cytosolic mtRNA release, thereby suppressing inflammation. Pharmacological activation of mitophagy with UA markedly improved lung pathology, reduced inflammatory cytokine levels, and inhibited excessive activation of the RIG-I/MDA5-MAVS pathway. Conversely, the knockdown of PINK1 or PRKN weakened the protective effects of UA. Both in vitro and in vivo, UA reduced radiation-induced inflammation and improved lung tissue structure and function through mitophagy. CONCLUSIONS: Radiation-induced mtRNA release activates the RIG-I/MDA5-MAVS-mediated type I interferon response, driving inflammation in RP. PINK1/PRKN-mediated mitophagy significantly alleviates inflammation by reducing cytosolic mtRNA release. As a mitophagy inducer, UA demonstrates therapeutic potential for RP, providing a new direction for the development of anti-inflammatory strategies.

doi.org/10.1016/j.intimp.2025.114671 PubMed 40253768 Interventions