Fufang Zhenzhu TiaoZhi (FTZ), a Chinese medicinal decoction, has continuously been used to treat metabolic syndrome. Atherosclerosis is the main pathological basis of cardiovascular disease. The N6 methyladenosine (m⁶A) modification is a highly dynamic and reversible process involving a variety of important biological processes. Here, we investigated the therapeutic effects and mechanism of FTZ in diabetes-accelerated atherosclerosis. Doppler ultrasonography was used to examine the carotid intima-media thickness and plaque area in diabetic atherosclerosis patients. HFD mice were injected with streptozotocin to induce diabetes. HE and Oil red O staining were used to assess the effect of FTZ on lipid deposition. HUVECs were induced with HG/ox-LDL as a model of diabetic atherosclerosis. Furthermore, application of m⁶A methylation level kit, qRT-PCR, Western blot, tunel staining, reactive oxygen species staining and mPTP staining were performed to analyze the detailed mechanism. Clinical trials of FTZ have shown obvious effect of lowering blood glucose and blood lipids. These effects were reversed after FTZ intervention. Compared with the control, lipid deposition decreased significantly after FTZ administration. FTZ reduced endothelial cell apoptosis. At the same time, we found that FTZ reversed the increase of methylation reader YTHDF2 caused by ox-LDL treatment. Subsequently, we discovered that YTHDF2 degraded SIRT3 mRNA, leading to endothelial cell apoptosis and oxidative stress. FTZ attenuated diabetes-accelerated atherosclerosis by decreasing blood glucose and serum lipids levels, and increased endothelial cell antioxidant capacity, inhibited endothelial cell apoptosis via inhibiting YTHDF2-mediated m6A modification of SIRT3 mRNA, which reduced mRNA degradation.

Research on the Chinese herbal formula Fufang Zhenzhu Tiaozhi (FTZ) has demonstrated its effectiveness in treating hyperlipidemia and glycolipid metabolic disorders. Additionally, FTZ has shown inhibitory effects on oxidative stress, regulation of lipid metabolism, and reduction of inflammation in these conditions. However, the precise mechanisms through which FTZ modulates macrophage function in atherosclerosis remain incompletely understood. Therefore, this study aims to investigate whether FTZ can effectively stabilize rupture-prone plaques by suppressing macrophage pyroptosis and impeding the development of M1 macrophage polarization in ApoE^-/- mice. To assess the impact of FTZ on macrophage function and atherosclerosis in ApoE^-/- mice, we orally administered FTZ at a dosage of 1.2 g/kg body weight daily for 14 weeks. Levels of interleukin-18 and interleukin-1β were quantified using ELISA kits to gauge FTZ's influence on inflammation. Total cholesterol content was measured with a Cholesterol Assay Kit to evaluate FTZ's effect on lipid metabolism. Aortic tissues were stained with Oil Red O, and immunohistochemistry techniques were applied to assess atherosclerotic lesions and plaque stability. To evaluate the effects of FTZ on macrophage pyroptosis and oxidative damage, immunofluorescence staining was utilized. Additionally, we conducted an analysis of protein and mRNA expression levels of NLRP3 inflammasome-related genes and macrophage polarization-related genes using RT-PCR and western blotting techniques. This study illustrates the potential therapeutic effectiveness of FTZ in mitigating the severity of atherosclerosis and improving serum lipid profiles by inhibiting inflammation. The observed enhancements in atherosclerosis severity and inflammation can be attributed to the suppression of NLRP3 inflammasome activity and M1 polarization by FTZ. The current findings indicate that FTZ provides protection against atherosclerosis, positioning it as a promising candidate for novel therapies targeting atherosclerosis and related cardiovascular diseases.

Atherosclerosis is a chronic systemic inflammatory disease that causes severe cardiovascular events. B cell lymphoma 2-associated athanogene (BAG3) was proven to participate in the regulation of tumor angiogenesis, neurodegenerative diseases, and cardiac diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the role of BAG3 in atherosclerosis and elucidate the potential molecular mechanism. In this study, ApoE^−/− mice were given a tail-vein injection of BAG3-overexpressing lentivirus and fed a 12-week high-fat diet (HFD) to investigate the role of BAG3 in atherosclerosis. The overexpression of BAG3 reduced plaque areas and improved atherosclerosis in ApoE^−/− mice. Our research proves that BAG3 promotes autophagy in vitro, contributing to the suppression of EndMT in human umbilical vein endothelial cells (HUVECs). Mechanically, autophagy activation is mediated by BAG3 via the interaction between BAG3 and its chaperones HSP70 and HSPB8. In conclusion, BAG3 facilitates autophagy activation via the formation of the chaperone-assisted selective autophagy (CASA) complex interacting with HSP70 and HSPB8, leading to the inhibition of EndMT during the progression of atherosclerosis and indicating that BAG3 is a potential therapeutic target for atherosclerosis.

N6-methyladenosine (m⁶A) plays a significant role as an epigenetic mechanism, which is involved in various cancers’ progress via regulating mRNA modification. As a crucial m⁶A “reader”, YTHDF1 is able to alter m⁶A-modified mRNA and promote the protein translation process in multiple cancers. However, the role of YTHDF1 in lung cancer has not been fully investigated. This study focuses on elucidating the function of YTHDF1 in the development of lung cancer and its underlying mechanism. We demonstrated that YTHDF1 was highly expressed in lung carcinoma progression; then, the loss of function experiments in lung cell lines confirmed that knockdown of YTHDF1 suppressed cell proliferation, migration and invasion and induced ferroptosis of lung cancer cells. Further functional assays showed that ferritin (FTH) was identified as the key target of YTHDF1 in lung cancer cells. Furthermore, the overexpression of ferritin in YTHDF1-depleted cells partially restored lung cancer cell suppression. Collectively, our data suggested that the upregulation of YTHDF1 promotes lung cancer carcinogenesis by accelerating ferritin translation in an m⁶A-dependent manner. We hope that our findings may provide a new target for lung cancer diagnosis and treatment.

Metabolic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), diabetes, and their multi-organ complications, are characterized by high prevalence, systemic involvement, and a lack of effective reversal strategies. Their pathological core involves energy metabolism imbalance, chronic inflammation, and multi-tissue injury. In recent years, Sterile Alpha and TIR Motif Containing 1 (SARM1), an NAD⁺ hydrolyzing signaling molecule, has been repositioned from a single executor of axonal degeneration to a cross system metabolic regulatory node. By depleting NAD⁺, disrupting mitochondrial homeostasis, and modulating neuroimmune signaling, SARM1 predominantly exerts pro-injury effects in obesity, NAFLD, cardiac disorders, and peripheral neuropathies. However, in specific cell types, such as hepatic stellate cells, its interaction dependent activity can suppress fibrosis, revealing a striking context dependent duality. Despite these findings, a systematic understanding of SARM1's cell-type-specific regulation, tissue heterogeneity and long-term intervention safety in metabolic diseases remains limited, thereby constraining its translational potential. This review outlines the structural characteristics and activation mechanisms of SARM1 and, for the first time, discusses its context-dependent roles in metabolic diseases. It also summarizes emerging pharmacological intervention strategies, including small-molecule inhibitors, natural product modulators, and agonists, aiming to provide a theoretical basis for precise interventions in metabolic diseases and to inspire novel therapeutic approaches.