Cover Credit: Schematic illustration of RVG-miR-23a/27a/26a-Exos for the treatment of diabetic nephropathy (DN). Delivery of miR-23a/27a/26a cluster by RVG-modified satellite cell-derived Exos could be a promising targeted treatment for DN. RVG-miR-23a/27a/26a-Exos could effectively ameliorate tubular injury and tubulointerstitial fibrosis (TIF) by a mechanism that synergistically targets several profibrotic regulators, which not only regulated miRNA cluster-targeting Lpp simultaneously, but controlled miR-27a-3p-targeting Zbtb20 and miR-26a-5p-targeting Klhl42, respectively. (DOI 10.1038/s41401-023-01140-4). See the article in pages 2455–2468

Cover Credit: The schematic diagram describes the mechanism of action of G-sHDL (gemcitabine-loaded synthetic high-density lipoprotein) in treating colorectal cancer with liver metastasis. G-sHDL can target and kill hepatic Mono-M2 (monocyte-derived alternatively activated macrophages) that may eradicate tumor antigen-specific CD8+ T cells, and can also induce ICD of tumor cells to prime the antitumor immunity. Consequently, G-sHDL would improve the number and activity of tumor antigen-specific CD8+ T cells and synergize with anti-PD-L1 antibody in treating colorectal cancer. (DOI 10.1038/s41401-023-01110-w). See the article in pages 2331–2341

Cover Credit: The schematic diagram of the mechanism underlying the regulation of monocyte migration and differentiation by β-arrestin2, further mediating hepatocyte apoptosis in autoimmune hepatitis. (DOI 10.1038/s41401-023-01103-9). See the article in pages 2048–2064

Cover Credit: Bergapten on NLRP3 inflammasome in inflammatory diseases

Inhibition of NLRP3 inflammasome activation produces potent therapeutic effects in a wide array of inflammatory diseases. The schematic describes that bergapten, a natural organic compound in herbal medicines and fruits, effectively inhibits NLRP3 inflammasome activation, cytokine release, and pyroptosis through maintenance of mitochondrial homeostasis by promoting mitophagy, suggesting its potential role in suppressing the inflammatory response. See the article in pages 1867–1878.

Cover Credit: Mechanisms of Takeda G protein-coupled receptor-5 (TGR5) agonist on inhibiting intestinal epithelial cell apoptosis and ameliorating ulcerative colitis. Activation of TGR5 by OM8 enhanced cAMP/PKA signaling, which led to upregulation of c-FLIP expression, and subsequently suppressed JNK phosphorylation, thereby antagonizing TNF-α induced intestinal epithelial cell apoptosis.

Cover Credit: Defect in branched-chain amino acid (BCAA) catabolism has been recognized as a metabolic hallmark and therapeutic target for heart failure. As BCAA catabolic enzymes express ubiquitously, it is important to determine the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in vivo. In this issue, Chen Gao and the colleagues explored the cardiomyocytes specific BCAA catabolic defects in vivo.

Pazopanib alleviates LPS-induced inflammation through the MEK4-JNK-AP-1 pathway. A schematic diagram shows our small molecule compound library screening, and the VEGFR inhibitor pazopanib inhibits microglial hyperactivation and protects dopaminergic neurons from neuroinflammation-induced cell death in vitro and in vivo. Pazopanib alleviates LPS-induced neuroinflammation by inhibiting the MEK4-JNK-AP-1 pathway.

Schematic depicting the role of AMPAR S-nitrosylation in the persistent anxiety following chronic pain and the potential therapeutic strategy. AMPAR trafficking by S-nitrosylation is enhanced in the vmPFC of mice with chronic pain-induced persistent anxiety after analgesic treatment. ZL006, an inhibitor of nNOS and PSD-95 interaction, rescues the persistent anxiety.

In the context demyelination, the transient receptor potential vanilloid 1 (TRPV1) is needed to facilitate the efficient clearance of myelin debris, a process that paves the way for subsequent remyelination. By employing loss-of-function and gain-of-function studies, we revealed that microglial function is highly affected in terms of the functional activity of TRPV1. Global activation of TRPV1 drives microglia to demyelinating sites and enhances microglial phagocytosis, whereas TRPV1-deficient microglia failed to do so. The scavenger receptor CD36 mediates the enhanced phagocytosis following TRPV1 activation in microglia, accompanied by potential metabolic shift with downregulation of glycolysis.

3-(2-bromo-4-hydroxyphenyl)-7-hydroxy-2H-chromen-2-one (SZC-6) is a novel SIRT3 activator that occupied allosite binding pocket of SIRT3 protein with high affinity. The cover art describes that SZC-6 showed significant protective effects on mitochondria, which would create a brighter future for new treatments for cardiac hypertrophy.

Schematic models of 14-deoxygarcinol (DOG) in attenuating adipose tissue inflammation. Therapeutically, DOG activates SIRT2 to suppress NF-κB/NLRP3 inflammasome-mediated IL-1β secretion, which in turn alleviates adipose tissue inflammation and improves insulin sensitivity.

Schematic depicting the preparation of a dual-responsive nanoparticle BCGN and its mechanisms in treating non-small-cell lung cancer (NSCLC). The BCGN are responsive to oxidation and reduction for triggering drug release at different conditions. It provides a promising strategy to improve combinational molecular targeted therapy against NSCLC.