Yuanli Chen

Vascular calcification represents an active multifactorial process that mirrors several key features of skeletal bone mineralization. Clinically, it is characterized by diminished arterial compliance and increased arterial wall stiffness, both of which serve as independent predictors of significant adverse cardiovascular events. The primary cellular mechanism involves the phenotypic transformation of contractile vascular smooth muscle cells (VSMCs) into osteo/chondrogenic‐like cells, which produce an extracellular matrix conducive to hydroxyapatite deposition. This transdifferentiation is regulated by intricate cellular signaling networks, including the BMP‐Smad signaling pathway, both canonical and non‐canonical Wnt/β‐catenin pathways, Stat3 activated by inflammatory cytokines, the Notch signaling pathway, and ROS‐activated MAPK (ERK/p38) and NF‐κB pathways. In contrast, the SIRT family proteins (such as nuclear SIRT1/SIRT6), extracellular pyrophosphate (PPi), and matrix Gla protein (MGP) exert inhibitory effects on vascular calcification. Anatomically, calcification can be localized to the intimal layer, often superimposed on advanced atherosclerotic plaques in large conduit arteries, or to the medial layer, a pattern characteristic of small‐ to medium‐sized muscular arteries, known as Mönckeberg's sclerosis. Despite extensive research efforts, the molecular mechanisms governing mineral deposition in vascular tissues remain inadequately understood, and no pharmacological intervention has yet been demonstrated to be both safe and effective in preventing or reversing established calcification. In this review, we examine current insights into the pathobiology of vascular calcification, critically evaluate available in vitro models (including human aortic smooth muscle cells, endothelial cells, and valvular interstitial cell calcification models) and in vivo models (such as pharmacologically induced and genetically modified or surgical models) and highlight emerging therapeutic targets and agents that are currently under preclinical or early clinical investigation.

This study presents mitogen-activated protein kinase kinase (MEK) inhibition as a strategy for cytokine release syndrome (CRS) and secondary haemophagocytic lymphohistiocytosis (sHLH) in chimeric antigen receptor (CAR)-T therapy, utilizing MEK's regulatory actions that target macrophage activation, cytokine secretion from both macrophages and CAR-T cells, supported by evidence of unimpaired CAR-T-cell therapeutic efficacy of alleviated CAR-T-related inflammation.

Aging is a major risk factor for diabetic kidney disease (DKD), with both conditions exhibiting similar renal pathology. We identify the energy-sensing molecule Retinoic acid-related orphan receptor γ (RORγ) as significantly downregulated in diabetic and aged kidneys. Tubule-specific RORγ deficiency exacerbates kidney injury, whereas its overexpression protects. Mechanistically, RORγ stabilizes insulin-induced gene 1 (INSIG1) by upregulating the deubiquitinase YOD1 and enhancing AMPK activity via CAB39, which together promote INSIG1 phosphorylation and subsequent stabilization. Stabilized INSIG1 potently blocks the ER-to-Golgi transport and activation of SREBP2 (cholesterol synthesis) and STING (inflammatory signaling). In diabetes, RORγ itself is suppressed transcriptionally by CTCF and functionally by impaired AMPK/SIRT1 signaling, which hinders its activation. Importantly, administration of a RORγ agonist or RORγ-enriched exosomes effectively alleviates diabetic kidney injury. Thus, RORγ emerges as a key regulatory node that mitigates DKD and renal aging by co-regulating AMPK-mediated metabolic and STING-driven innate immune pathways through INSIG1 stabilization.

Phenotypic abnormalities in vascular smooth muscle cells (VSMCs) are believed to play essential roles in the progression of vascular diseases. Here, we explored the impact of fibroblast growth factor 21 (FGF21) on the phenotypic transition of VSMCs. Our findings revealed that FGF21 expression was substantially down-regulated in both human and mouse neointimal regions. Additionally, plasma FGF21 levels were lower in patients with atherosclerotic coronary artery disease (ASCAD) compared to those without ASCAD. Similarly, patients with restenosis exhibited reduced FGF21 levels compared to those without restenosis. In vivo, FGF21 deficiency accelerated intimal hyperplasia and decreased the number of contractile VSMCs in mouse neointima. However, hepatocyte-specific FGF21 knockout had no effect on ligation-induced intimal hyperplasia. Conversely, administration of recombinant FGF21 protein reduced neointima formation. This effect was abolished in mice with β-klotho VSMC-specific knockout, suggesting a direct effect of FGF21 on VSMCs. In vitro, FGF21 could promote the contractile phenotype transition of human aortic smooth muscle cells under basal or platelet-derived growth factor-BB incubation conditions. Furthermore, FGF21 activation led to the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which subsequently formed a complex with the serum response factor (SRF)–myocardin complex. This complex increased the phosphorylation of SRF at serine 224, thereby enhancing the transcription activation of the SRF–myocardin complex. Finally, we revealed that treatment with the FGF21 analog efruxifermin or activation of p38 MAPK using anisomycin effectively inhibited neointima formation. Taken together, these results indicate that modulating FGF21 or its subsequent signal pathways could serve as a therapeutic strategy for vascular diseases characterized by abnormal VSMC phenotypic transition.

Introduction: Cluster of differentiation 36 (CD36) is highly expressed in the liver of patients with metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatohepatitis (MASH). However, the precise role of CD36 in MAFLD/MASH is controversial. In the current study, we aimed to uncover the role of CD36 in the early stage of MAFLD/MASH induced by high-fat diet (HFD) and methionine/choline-deficient (MCD) diet.Methods: CD36^−/− mice and littermate control mice were fed a normal food diet (NCD); HFD or MCD diet for 6 weeks.Results: We determined that CD36 deficiency attenuated HFD-induced hepatic steatosis while exacerbating MCD diet-induced steatohepatitis. Mechanistically, CD36 deficiency reduced HFD-induced expression of fatty acid synthase (FASN), sterol regulatory element binding protein 1c (SREBP1c), and acetyl-CoA carboxylase alpha (ACC1), thereby inhibiting de novo fatty acid synthesis. The expression of superoxide dismutase and genes involving fatty acid oxidation was inhibited by MCD diet. CD36 deficiency reduced expression of genes involving fatty acid oxidation, while MCD diet had no effect on these genes expression in CD36^−/− mice. Meanwhile, MCD diet-reduced superoxide dismutase expression was further inhibited by CD36 deficiency. Thus, MCD-induced liver ROS and inflammation were further enhanced by CD36 deficiency. By liver lipidomic analysis, we found that the levels of triglyceride (TG), diacylglycerols (DG), acylcarnitine (AcCA), ceramide (Cer) and LPC were increased, while phosphatidylcholine/phosphatidylethanolamine (PC/PE) were decreased in MCD diet-treated CD36^−/− mice compared with MCD diet-treated wild type mice. Indeed, the expression of serine palmitoyltransferase 2 (SPTLC2), the key rate-limiting enzyme of ceramide synthesis, was higher in CD36^−/− mice.Discussion: CD36 deficiency improves HFD-induced MAFLD by inhibiting fatty acid synthesis, while accelerating MCD diet-induced MASH via promoting Cer, LPC, TG and DG accumulation to accelerate liver inflammation. The complex role of CD36 in MAFLD/MASH needs more investigation to discover the precise and effective strategy when targeting CD36.

Vascular smooth muscle cell (VSMC) phenotype transformation significantly contributes to vascular intimal hyperplasia. However, effective preventive and therapeutic measures are lacking. Colchicine, a binary alkaloid derived from Colchicum autumnale, is traditionally used for treating inflammatory diseases. Its role in neointima formation is not fully understood. Here, we investigated the role of colchicine in vascular intimal hyperplasia. We found that colchicine significantly reduced vascular intimal hyperplasia in an animal model at 7, 14, and 28 days post carotid artery ligation and increased the number of contractile-phenotype VSMCs (SMA-positive cells) in the neointimal areas. In vitro experiments demonstrated that colchicine facilitated the transition of VSMCs from a proliferative phenotype to a contractile phenotype. Additionally, colchicine attenuated PDGF-BB-induced phenotypic conversion and upregulated the expression of serum response factor (SRF) and myocardin (MYOCD). Further molecular mechanistic studies revealed that colchicine inhibited the expression of forkhead box protein O3A (FOXO3A) to increase the activation of the SRF‒MYOCD complex. FOXO3A can bind to MSX1/2, thereby inhibiting the expression of SRF–MYOCD and contractile genes. Moreover, colchicine maintains vascular homeostasis and stabilizes the contractile phenotype by affecting the expression of autophagy-related genes (LC3II, p62, and Beclin-1) induced by FOXO3A. Additionally, colchicine inhibited monocyte/macrophage infiltration and inflammatory cytokine expression. In summary, this study suggests that colchicine inhibits vascular intimal hyperplasia by modulating FOXO3A-mediated SRF-MYOCD activation and autophagy, providing new insights for future therapeutic approaches targeting occlusive vascular diseases.