Mitochondrial Metabolic Regulation of Macrophage Polarization in Osteomyelitis and Other Orthopedic Disorders: Mechanisms and Therapeutic Opportunities

Jinglin Li^1,2Lin Zhang^1,2Jiaze Peng^1,2Chuntao Zhao³Wenguang Li⁴Yang Yu^1,2Xianpeng Huang^1,2Fuyin Yang^1,2Xuan Deng^1,2Xuxu Yang^1,2Tao Zhang^5*Jiachen Peng^1,2*

• ¹Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, China
• ²Joint Orthopaedic Research Center of Zunyi Medical University,Joint Orthopaedic Research Center of Zunyi Medical University, University of Rochester Medical Center, Zunyi, Guizhou Province, China
• ³Department of Orthopedic Surgery, The 920th Hospital of Joint Logistics Support Force, Kunming, Yunnan Province, China
• ⁴Bijie City First People's Hospital, Bijie, Guizhou, China
• ⁵Key Laboratory of Cell Engineering of Guizhou Province, Affiliated Hospital of Zunyi Medical University, 遵义市, China

Osteomyelitis is a complex infectious bone disease involving pathogen invasion, host immune responses, and dysregulation of the local microenvironment. As a critical component of the innate immune system, macrophages play a pivotal role in inflammatory responses and tissue repair. Their polarization states (M1/M2) directly influence disease progression, while mitochondrial metabolism, as the central hub of cellular energy metabolism, has recently been shown to play a key role in macrophage polarization and functional regulation. However, how mitochondrial metabolism regulates macrophage polarization to affect the pathological mechanisms of osteomyelitis, and how to develop novel therapeutic strategies based on this mechanism, remain critical scientific questions to be addressed. This review systematically summarizes the molecular mechanisms by which mitochondrial metabolism regulates macrophage polarization and its role in osteomyelitis, with a focus on the impact of mitochondrial dynamics (fission/fusion), metabolic reprogramming, and reactive oxygen species (ROS) generation on macrophage polarization. Additionally, potential therapeutic strategies targeting mitochondrial metabolism are analyzed. For the first time, this review integrates the interplay between mitochondrial metabolism and macrophage polarization in osteomyelitis, revealing how mitochondrial dysfunction exacerbates inflammation and bone destruction through metabolic reprogramming.Based on these findings, we propose novel therapeutic strategies targeting mitochondrial metabolism, offering new perspectives and directions for understanding the pathogenesis and clinical treatment of osteomyelitis.