Oxidative Signaling in Photodynamic Therapy: Interplay Between Ferroptosis and Mitophagy

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality that relies on the activation of photosensitizers (PS) by specific wavelengths of light to generate reactive oxygen species (ROS), resulting in localized cytotoxicity with relative sparing of healthy tissues. Depending on the PS properties, light dose, and intrinsic cellular features, PDT can elicit multiple cell death pathways, including apoptosis, necrosis, and autophagy. Increasing evidence indicates that PDT is also a potent inducer of ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation (LPO), glutathione (GSH) depletion, and inactivation of glutathione peroxidase 4 (GPX4). PDT-derived ROS promote ferroptosis both indirectly by exhausting antioxidant defenses and directly by peroxidizing PUFAs within membrane phospholipids. At the same time, intense oxidative stress generated by PDT can activate adaptive responses such as mitophagy, a selective autophagic process that removes damaged mitochondria to limit ROS production and preserve redox homeostasis. Ferroptosis and mitophagy are therefore tightly interconnected, functioning as opposing yet complementary regulators of cell fate. PDT emerges as a key upstream modulator of the ferroptosis–mitophagy balance, as spatially and temporally confined oxidative stress can shift cellular responses from adaptive mitochondrial quality control to irreversible ferroptotic injury. Despite growing interest in both PDT and ferroptosis, their mechanistic interplay, particularly in relation to mitophagy, remains underexplored. This narrative review provides an integrated overview of current knowledge on how PDT influences ferroptosis and mitophagy, highlighting the molecular mechanisms that connect these pathways and discussing their implications for improving therapeutic efficacy and overcoming resistance.