Targeting the Crosstalk Between Mitochondrial Homeostasis and Macrophage Polarization Through Natural Products: A Promising Approach for Diabetic Nephropathy Treatment

Diabetic nephropathy (DN) is a major microvascular complication of diabetes and a leading cause of kidney failure worldwide. Despite advances in disease-modifying therapies, a substantial residual risk of disease progression remains. Growing evidence suggests that mitochondrial dysfunction and macrophage-associated inflammatory responses are interconnected in DN. Disturbances in mitochondrial redox homeostasis, dynamics, biogenesis, mitophagy, and metabolism may promote inflammatory activation, whereas macrophage-derived inflammatory signals can further aggravate mitochondrial injury, potentially forming a feed-forward pathogenic network. This review summarizes the major mechanisms of mitochondrial dysfunction and macrophage polarization in DN and discusses the potential crosstalk between these processes. We further evaluate current pharmacological strategies targeting mitochondrial and inflammatory pathways and synthesize experimental evidence on natural products that modulate mitochondrial homeostasis, macrophage polarization, or related inflammatory signaling. Despite encouraging preclinical findings, clinical translation of natural products remains limited by chemical complexity and standardization challenges, uncertain pharmacokinetics and tissue exposure, incomplete causal target validation, safety and drug–drug interaction concerns, and a lack of high-quality clinical evidence. Overall, targeting mitochondrial–macrophage crosstalk represents a promising therapeutic framework for DN, but its clinical relevance requires further rigorous mechanistic, pharmacological, and clinical validation.