Dual Roles of Autophagy in Radiation-Induced Brain Injury: Mechanistic Insights and Therapeutic Implications

Cranial radiotherapy, while essential for treating brain tumors, often leads to radiation-induced brain injury, a debilitating condition marked by cognitive decline and neuronal damage. Autophagy, a key cellular process for recycling damaged organelles and proteins, has emerged as both a protective and detrimental player in radiation-induced brain injury.

This review systematically explores the dualistic role of autophagy in radiation-induced brain injury, synthesizing insights on its interplay with apoptosis, ferroptosis, neuroinflammation, oxidative stress, the blood-brain barrier, mitophagy, endoplasmic reticulum stress, and mitochondrial biogenesis.

While autophagy supports neuronal resilience by mitigating oxidative and inflammatory stress, excessive or dysregulated autophagy can lead to autophagic cell death and exacerbate injury. Pharmacological modulators such as mTOR inhibitors, AMP-activated protein kinase activators, demonstrate therapeutic potential in preclinical settings.

By elucidating the mechanistic underpinnings of autophagy in radiation-induced brain injury, this review underscores its dual roles and therapeutic relevance, offering a foundation for targeted interventions that optimize autophagic balance to protect brain function postradiotherapy.