Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation, immune dysregulation, oxidative stress, and impaired epidermal barrier function. In the present study, we investigated the protective effects of Tempol, a membrane-permeable nitroxide with antioxidant and anti-inflammatory properties, using several psoriasiform models. In HaCaT keratinocytes, stimulation with a cytokine mixture significantly induced inflammatory responses. Tempol (0.5 and 1 mM) showed no cytotoxic effects and markedly reduced the mRNA and protein levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6. Tempol was associated with reduced expression of TLR4, MyD88, TRAF6, and nuclear factor-kappa B (NF-κB), together with restoration of IκBα expression, findings consistent with modulation of the TLR4/NF-κB signaling pathway. In parallel, Tempol was associated with activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 antioxidant axis, as evidenced by increased expression of Nrf2, HO-1, and MnSOD, along with a reduction in the pro-oxidant enzymes NOX2 and NOX4. These effects were associated with decreased oxidative damage, including reduced lipid peroxidation and nitric oxide production. Furthermore, Tempol exerted cytoprotective effects by restoring the balance between pro- and antiapoptotic markers, as indicated by increased Bcl-2 levels, decreased Bax and p53 expression, and a reduced Bax/Bcl-2 ratio. The anti-inflammatory activity of Tempol was further confirmed in an imiquimod (IMQ)-stimulated HaCaT/THP-1 coculture model, where it significantly reduced the release of key immune mediators, including TLR4, IL-8, IL-17A, and IL-23, highlighting its ability to modulate immune-epithelial crosstalk. In a reconstructed human epidermis (RHE) model, Tempol preserved tissue viability under psoriasiform conditions and significantly reduced Staphylococcus aureus (S. aureus) adhesion. Importantly, Tempol restored epidermal barrier integrity, as demonstrated by increased levels of tight junction and differentiation markers, including ZO-1, Occludin, Claudin-1, and Filaggrin, even under infection-associated conditions. Taken as a whole, these findings support the potential of Tempol as a promising therapeutic strategy for psoriasis and related inflammatory skin disorders.

Metabolic diseases are characterized by profound dysregulation of the immunometabolic network, in which the interplay between chronic inflammation and metabolic disturbances form a self-amplifying vicious cycle that drives disease progression. disease progression. Triggering receptor expressed on myeloid cells 2 (TREM2), a central regulator of immunometabolism, interacts with the adaptor protein DAP12 to orchestrate key macrophage functions including polarization, phagocytic clearance, inflammation resolution, and metabolic reprogramming. Through these processes, TREM2 plays a critical role in sensing metabolic stress signals and maintaining immunometabolic homeostasis. In this review, we systematically summarize recent advances in understanding the roles of TREM2 in major metabolic diseases, including atherosclerosis (AS), diabetes mellitus and its complications, obesity, and non-alcoholic steatohepatitis (NASH), while highlighting its functional heterogeneity across different diseases contexts. We further dissect the regulatory mechanisms governing TREM2 activity, with particular emphasis on cell subset-specific expression patterns, microenvironmental signal interactions, and post-translational modifications (PTMs). Moreover, we summarize emerging TREM2-targeted therapeutic strategies, including soluble TREM2 (sTREM2), agonistic antibodies, and traditional Chinese medicine (TCM)-based approaches, and evaluate the translational potential of sTREM2 as a noninvasive biomarker. Emerging research frontiers involving TREM2, such as the gut microbiota-metabolism axis and interorgan communication, are also discussed. Finally, we identify key unresolved questions and future research priorities, providing a theoretical framework and potential strategies for precision diagnosis and targeted intervention in metabolic diseases.

Myocarditis is characterized by inflammatory cell infiltration and myocardial injury, yet current treatments remain largely empirical and nonspecific. Given the heart's high energy demand and the essential role of mitochondria in cellular metabolism, investigating mitochondria-related genes may provide novel therapeutic insights. In this study, we integrated bulk RNA sequencing data from CVB3 viral myocarditis (VMC) model with mitochondrial gene sets from MitoCarta3.0 and human myocarditis-related genes from GeneCards. Through comprehensive bioinformatics analyses, including weighted gene coexpression network analysis (WGCNA), random forest (RF), and SHapley Additive exPlanations (SHAP), we identified mitochondrial metabolism-related genes associated with myocarditis. Single-cell RNA sequencing (scRNA-seq) analysis further revealed that macrophages were the predominant infiltrating immune population, with Tspo expressed in myocarditis macrophages. Tspo knockdown enhanced inflammatory responses and disrupted mitochondrial structure and function, whereas treatment with the Tspo ligand Ro5-4864 exerted the opposite effects. Consistently, administration of Ro5-4864 in a VMC mouse model mitigated inflammation and preserved cardiac function. Collectively, our findings identify Tspo as a novel mitochondria-associated protective response factor in myocarditis, providing new insights into its pathophysiological mechanisms and highlighting Tspo as a promising therapeutic target for future intervention.

Protein fragments are increasingly recognized as both biomarkers and therapeutic targets, offering important insights into disease mechanisms and potential intervention strategies. Evidence from in vitro and in vivo studies indicates that these fragments are not merely degradation products but possess distinct biological activities, actively modulating immune signaling and contributing to both acute and chronic inflammatory processes. Here, we provide an overview of proteases and their inhibitors, with a particular focus on peptide fragments generated through proteolytic cleavage. Special emphasis is placed on fragments derived from α1-antitrypsin (AAT), an acute-phase glycoprotein and major inhibitor of neutrophil elastase and other serine proteases. AAT-derived peptides of varying lengths, generated by both target and nontarget proteases, including metalloproteases, have been detected in human biological fluids and tissues. Beyond reflecting proteolytic activity, these peptides provide clinically relevant information on disease-associated inflammation and tissue remodeling. Accordingly, they are emerging as promising diagnostic, monitoring, and predictive biomarkers. Here, we summarize current knowledge on cleaved AAT fragments, their biological functions, and their potential clinical applications.