Photobiomodulation Targets Mitochondrial Homeostasis for Diabetic Wound Healing

Abstract

Diabetes mellitus is a global public health problem, and impaired wound healing is a complication that significantly reduces patients’ quality of life. Dysregulation of mitochondrial homeostasis is a key pathological feature contributing to impaired wound healing in diabetes. This dysregulation increases oxidative stress, resulting in impaired energy metabolism, endothelial dysfunction, and prolonged inflammatory responses. Photobiomodulation (PBM) is a noninvasive therapy that has been successfully used to promote diabetic wound healing by modulating mitochondrial homeostasis via multiple mechanisms. In this review, we have systematically summarized the following roles of PBM in restoring mitochondrial homeostasis to accelerate diabetic wound healing: improving mitochondrial dysfunction and oxidative stress through cytochrome C oxidase in the electron transport chain, thereby enhancing oxidative phosphorylation and adenosine triphosphate production; modifying mitochondrial dynamics by inhibiting the expression of dynamin-related protein 1 and promoting mitofusin-2 expression to restore mitochondrial morphology and function; reducing inflammation and promoting macrophage polarization from the M1 to M2 phenotype; activating signaling pathways (e.g., VEGF, PI3K/AKT/mTOR/GSK3-β, AMPK, RAS/MAPK, JAK/STAT, NF-κB, TGF-β/Smad) to enhance cell proliferation and angiogenesis and resolve inflammation. Beyond monotherapy, this review synthesizes the burgeoning field of PBM in combination with advanced therapeutic strategies, such as hydrogels, nanomaterials, small-molecule drugs, adipose-derived stem cells, and extracellular vesicles, highlighting their synergistic potential for enhanced efficacy. Finally, this review critically addresses the prevailing challenges in clinical translation, particularly the lack of standardized treatment parameters, and proposes future research directions. This comprehensive overview aims to solidify the scientific foundation of PBM and inspire the design of integrated, precision therapeutic strategies for diabetic wound management.

Impact Statement

This review delineates the critical role of photobiomodulation (PBM) for overcoming diabetic wound healing impairment by restoring mitochondrial homeostasis. It integrates multifaceted evidence on the mechanisms of PBM—from improving cellular energetics and redox balance to modulating inflammation and activating prohealing pathways. Furthermore, it systematically explores the combination of PBM with next-generation therapeutic strategies. These insights not only advance the fundamental understanding of PBM but also directly inform the rational design of novel, effective treatments for diabetic chronic wounds, a major unmet clinical need.