Background: The AMPK/SIRT1/PGC‐1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target. Methods: We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms—including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease—to dissect its tissue‐specific pathophysiological impacts. Results: The AMPK/SIRT1/PGC‐1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC‐1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease‐specific mechanisms: promoting Aβ production via BACE1/γ‐secretase in Alzheimer's; impairing α‐synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF‐β/Smad3 signaling. Conclusions: The AMPK/SIRT1/PGC‐1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies—including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)—offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue‐specific regulatory mechanisms, such as AMPK isoform diversity and PGC‐1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders.

Macrophage polarization represents a fundamental plasticity process within innate immunity, profoundly influencing tissue homeostasis and disease progression. Based on developmental origins, macrophages are categorized into tissue-resident macrophages and monocyte-derived macrophages, which collectively form a dynamic host defense network. Notably, the functional states of macrophages exist along a continuum, extending beyond the classical pro-inflammatory (M1) and anti-inflammatory/reparative (M2) dichotomy. These states are dynamically shaped by spatiotemporally heterogeneous microenvironmental signals and coordinated through intricate molecular networks. Key signaling pathways guide polarization directions. Metabolic reprogramming, where M1 polarization relies on glycolysis and the pentose phosphate pathway while M2 polarization favors oxidative phosphorylation and fatty acid oxidation, not only supplies energy but also generates regulatory metabolites. Furthermore, epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, contribute to stabilizing polarized phenotypes. These mechanisms are interconnected, forming feedback loops that collectively sculpt macrophage functional diversity. Dysregulated polarization underlies numerous diseases. In response, therapeutic strategies targeting macrophage polarization are rapidly emerging. These include pharmacological interventions using small molecules and metabolic modulators to reprogram cell phenotypes, immunotherapies such as CAR-M macrophages or exosome-mediated reprogramming to remodel immune microenvironments, and precision regulation through gene editing or epigenetic modifications. Although innovations like single-cell omics, spatial transcriptomics, computational modeling, and synthetic biology are advancing the field, clinical translation still faces challenges including off-target effects, inefficient delivery, microenvironmental dependency. Future research must integrate multi-omics data to develop individualized therapies, further investigate the stability and plasticity of polarization states, and leverage smart materials and advanced model systems to advance precision immunotherapeutics.

Diabetic nephropathy (DN) has become the primary cause of end-stage renal disease globally, and its epidemiological burden intensifies alongside the surging prevalence of diabetes. The pathogenesis involves complex interactions among metabolic dysregulation, oxidative stress, inflammatory responses, and fibrotic signaling pathways. Hyperglycemia drives renal injury through activation of the RAAS and accumulation of advanced glycation end products (AGEs), while aberrant activation of key signaling pathways such as TGF-β/Smad3 and NF-κB further promotes renal fibrosis. Current clinical diagnosis primarily relies on proteinuria and glomerular filtration rate indicators, yet their insufficient sensitivity for early renal injury leads to high underdiagnosis rates of nonproteinuric DN. Traditional therapy, centered on renin-angiotensin system blockers, can delay disease progression but fails to reverse renal fibrosis. Recent years have witnessed significant therapeutic breakthroughs. These include SGLT2 inhibitors improving glomerular hypertension via mechanisms independent of glucose-lowering, novel anti-inflammatory and anti-fibrotic agents such as nonsteroidal mineralocorticoid receptor antagonists targeting TGF-β/Smad3 pathway inhibition, and multi-target traditional Chinese medicine interventions offering comprehensive protection by regulating signaling networks like PI3K/Akt and AGE-RAGE. At the molecular level, research reveals that inflammation and immune dysregulation, oxidative stress and metabolic disorders, epigenetic modifications, and cellular structural and functional damage collectively form the intricate pathological network of diabetic nephropathy. Emerging technologies like nanodrug delivery systems, stem cell therapy, and gene editing show broad prospects for precise interventions targeting specific molecular pathways. Future research must integrate multi-omics technologies to deeply dissect disease heterogeneity, develop efficient biomarkers for early diagnosis, and optimize therapeutic efficacy through innovative drug delivery systems, while strengthening evidence-based validation of integrated traditional Chinese and Western medicine strategies. This approach will provide novel insights for the precise prevention and control of diabetic nephropathy.