Diabetic nephropathy (DN), one of the most common and severe microvascular complications of diabetes, significantly increases the risk of renal failure and cardiovascular events. A high-glucose environment can lead to mitochondrial dysfunction in macrophages, which, through remodeling of energy metabolism, mediates the polarization of a pro-inflammatory phenotype and contributes to the formation of a chronic inflammatory microenvironment. Recent studies have found that high-glucose stimulation induces dysregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) redox pathway in macrophages, leading to the generation of oxidative stress (OS) that further drives chronic inflammation. Therefore, it is crucial to fully understand how OS affects macrophage phenotypes and functions following NRF2 inhibition. This review analyzes the role of OS induced by NRF2 dysfunction in the chronic inflammation of DN and explores the relationship between OS and macrophage mitochondrial energy metabolism through the NAD⁺/NADH-SIRT3 axis, providing new therapeutic targets for targeting OS to improve the inflammatory microenvironment and vascular damage in DN.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and, with increasing research on the tumor immune microenvironment (TIME), the immunosuppressive micro-environment of HCC hampers further application of immunotherapy, even though immunotherapy can provide survival benefits to patients with advanced liver cancer. Current studies suggest that polyamine metabolism is not only a key metabolic pathway for the formation of immunosuppressive phenotypes in tumor-associated macrophages (TAMs), but it is also profoundly involved in mitochondrial quality control signaling and the energy metabolism regulation process, so it is particularly important to further investigate the role of polyamine metabolism in the tumor microenvironment (TME). In this review, by summarizing the current research progress of key enzymes and substrates of the polyamine metabolic pathway in regulating TAMs and T cells, we propose that polyamine biosynthesis can intervene in the process of mitochondrial energy metabolism by affecting mitochondrial autophagy, which, in turn, regulates macrophage polarization and T cell differentiation. Polyamine metabolism may be a key target for the interactive dialog between HCC cells and immune cells such as TAMs, so interfering with polyamine metabolism may become an important entry point to break intercellular communication, providing new research space for developing polyamine metabolism-based therapy for HCC.

Systemic chronic inflammation (SCI) due to intrinsic immune over-activation is an important factor in the development of many noninfectious chronic diseases, such as neurodegenerative diseases and diabetes mellitus. Among these immune responses, macrophages are extensively involved in the regulation of inflammatory responses by virtue of their polarization plasticity; thus, dysregulation of macrophage polarization direction is one of the potential causes of the generation and maintenance of SCI. High-temperature demand protein A2 (HtrA2/Omi) is an important regulator of mitochondrial quality control, not only participating in the degradation of mis-accumulated proteins in the mitochondrial unfolded protein response (UPRmt) to maintain normal mitochondrial function through its enzymatic activity, but also participating in the regulation of mitochondrial dynamics-related protein interactions to maintain mitochondrial morphology. Recent studies have also reported the involvement of HtrA2/Omi as a novel inflammatory mediator in the regulation of the inflammatory response. HtrA2/Omi regulates the inflammatory response in BMDM by controlling TRAF2 stabilization in a collagen-induced arthritis mouse model; the lack of HtrA2 ameliorates pro-inflammatory cytokine expression in macrophages. In this review, we summarize the mechanisms by which HtrA2/Omi proteins are involved in macrophage polarization remodeling by influencing macrophage energy metabolism reprogramming through the regulation of inflammatory signaling pathways and mitochondrial quality control, elucidating the roles played by HtrA2/Omi proteins in inflammatory responses. In conclusion, interfering with HtrA2/Omi may become an important entry point for regulating macrophage polarization, providing new research space for developing HtrA2/Omi-based therapies for SCI.

Plant-derived vesicles offer several advantages, including high yield, low cost, ethical compatibility, safety, and potential health benefits. These advantages enable them to overcome technological limitations associated with vesicles of mammalian origin. Ginseng, a prominent example of a natural botanical plant, is known for its abundant bioactive components. Recent studies confirmed that ginseng-derived vesicles offer significant advantages in the treatment of human diseases. Therefore, this study reviews the extraction and purification processes of ginseng-derived vesicle-like nanoparticles (GDVLNs), their therapeutic potential, and the active ingredients in GDVLNs that may exert pharmacological activities. Furthermore, this study evaluates the research and applications of nanosized ginseng extracts, with a primary focus on ginsenosides.