Sympathetic nervous system (SNS) imbalance is a common pathological basis for cardiovascular diseases, non-alcoholic fatty liver disease, and diabetes. This review focuses on these diseases, analyzing two core mechanisms: excessive sympathetic excitation induced by endoplasmic reticulum stress (ERS) or autophagy dysfunction in key central nuclei (e.g., hypothalamus, rostral ventrolateral medulla); and ERS/autophagy abnormalities in peripheral target organs caused by chronic SNS overactivation. Existing studies confirm that chronic SNS overactivation promotes peripheral metabolic overload via sustained catecholamine release, inducing persistent ERS and disrupting the protective unfolded protein response (UPR)–autophagy network, ultimately leading to cell apoptosis, inflammation, and fibrosis. Notably, central ERS or autophagy dysfunction further perturbs autonomic homeostasis, exacerbating sympathetic overexcitation. This review systematically elaborates on SNS overactivation as a critical bridge mediating UPR–autophagy network dysregulation in central and peripheral tissues, and explores therapeutic prospects of targeting key nodes (e.g., chemical chaperones, specific UPR modulators, nanomedicine), providing a theoretical basis for basic research and clinical translation.

Cyanidin-3-O-Glucoside (C3G) is the primary anthocyanin-active component in bilberry, exhibiting various pharmacological activities such as antioxidant, anti-inflammatory, and lipid metabolism-regulating effects. To address the clinical need for non-alcoholic fatty liver disease (NAFLD) prevention and treatment, this study aimed to investigate the ameliorative effects of C3G on NAFLD pathology and elucidate its molecular mechanisms of protection via the AMPK pathway. After a one-week acclimatization period, 20 six-week-old SPF mice were randomly divided into four groups: normal diet control (NCD), high-fat diet model (HFD), HFD + L-C3G (100 mg/kg/day), and HFD + H-C3G (200 mg/kg/day). Except for the NCD group, the remaining groups were fed a 60% high-fat diet for four weeks to establish an early-stage NAFLD model, with successful model construction verified by weight and liver weight gain. From the fifth week onward, C3G groups received daily administration for four consecutive weeks, while control groups were given an equal volume of distilled water. Liver function, lipid metabolism, oxidative stress, and inflammatory levels were assessed using ELISA, H&E staining, and other methods. The results showed that C3G restored liver function in NAFLD mice, improved lipid metabolism disorders, reduced oxidative stress and inflammatory responses, and alleviated liver pathological damage. Mechanistic studies revealed that C3G regulated the expression of mRNA and proteins related to the AMPK/SIRT1/NF-κB signaling pathway, activating the pathway by upregulating AMPK and its upstream regulators while inhibiting NF-κB-mediated inflammatory responses. This study confirmed that C3G can ameliorate high-fat diet-induced NAFLD lesions by activating the AMPK/SIRT1/NF-κB pathway, providing a potential intervention strategy for NAFLD prevention and treatment.

Hypertension is the leading global risk factor for cardiovascular diseases, and its pathogenesis is closely linked to excessive sympathetic activation, which markedly elevates the risk of stroke, heart failure and other adverse cardiovascular events. Traditional therapies mainly target peripheral mechanisms, whereas the clinical efficacy of renal denervation highlights the critical role of central regulation in sympathetic hyperactivity. This review focuses on the core sympathetic nuclei including the rostral ventrolateral medulla (RVLM) and paraventricular nucleus (PVN), with epigenetic regulation as a key innovative perspective. We systematically summarize the upstream driving effects of reactive oxygen species (ROS) and neuroinflammation, and emphasize lncRNA/miRNA-mediated post-transcriptional regulation and the modulatory actions of gasotransmitters. Under stress conditions, aberrant activation of ROS and neuroimmune pathways, epigenetic reprogramming, and hyperexcitability of central sympathetic neurons act as key events in sympathetic overactivation, which interact synergistically to promote hypertension. Integrating evidence from multiple hypertensive animal models and clinical studies, we discuss multimodal interventions including pharmacotherapy, nanozyme biotechnology and neuromodulation, analyze current translational challenges, and provide a theoretical framework for developing central-targeted antihypertensive therapies.

Celastrol (CSL), a natural triterpenoid extracted from Tripterygium wilfordii, demonstrates a wide range of biological activities. In this study, we explored whether CSL alleviates kidney damage in spontaneously hypertensive rats (SHRs) through the modulation of the Nrf2/Ho-1 pathway, a crucial target in renal injury models. A total of 40 male SHRs, aged 6–8 weeks, were randomly allocated to four groups: the control group (CON, serving as the healthy control), the spontaneously hypertensive rat group (SHR), the SHR group treated with low-dose CSL (L-CSL + SHR, 0.5 mg/kg/d), and the SHR group treated with high-dose CSL (H-CSL + SHR, 1 mg/kg/d). All drugs were formulated using physiological saline as the solvent and administered via intraperitoneal injection. The control group received an equivalent volume of physiological saline via intraperitoneal injection, and all groups underwent continuous daily administration for 6 weeks. The results indicated that, in comparison with the control group, the serum levels of angiotensin, angiotensin-converting enzyme, and aldosterone in the SHR group were relatively high, and CSL treatment further downregulated these indices. Simultaneously, CSL downregulated pro-inflammatory factors (tumor necrosis factor-α and interleukin-1β) and upregulated interleukin-6. Regarding renal function-related indicators, CSL reduced malondialdehyde levels and enhanced the activities of antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, and catalase. Moreover, CSL inhibited the overexpression of Keap1. Significantly, the mRNA levels of Nrf2, Nqo1, and Ho-1 in the CSL-treated groups were notably higher than those in the SHR group. These findings suggest that CSL mitigates renal pathological damage in SHR by activating the Nrf2/Ho-1 pathway, offering a potential therapeutic approach for hypertension-induced renal injury.

Mechanosensitive Piezo1 channels participate in regulating pain sensitivity, insulin secretion, and vascular tension; however, their expression in the autonomic paraventricular nucleus (PVN) and role in modulating sympathetic outflow and cardiovascular function remain unstudied. In this study, unilateral PVN microinjection of the Piezo1 channel blocker Dooku1 (0.1, 1, 10, 100, and 200 pmol) administered to anesthetized male rats increased renal sympathetic nerve activity (RSNA) and mean artery pressure (MAP) in a dose-dependent manner, with maximum increases of 93 ± 30% (p < 0.0001) and 21 ± 5 mmHg (p < 0.0001), respectively, elicited by Dooku1 at 100 pmol. Similarly, PVN microinjection of the peptide Piezo1 channel blocker GsMTx4 (1 nmol) significantly increased RSNA (p < 0.001) and MAP (p < 0.0001). Conversely, PVN-microinjected Piezo1 channel activators Yoda1 (5 nmol) and Jedi2 (5 nmol) did not significantly alter RSNA or MAP. Western blot and qRT-PCR analyses of the hypothalamic PVN showed abundant Piezo1 mRNA and protein expression. Immunofluorescence detection showed that Piezo1 was expressed in pre-sympathetic PVN neurons with axons projecting to the rostral ventrolateral medulla. We conclude that Piezo1 channels expressed in the autonomic PVN neurons play an important role in regulating sympathetic outflow and cardiovascular function.

Excessive activation of the sympathetic nervous system is a prominent contributor linked to heart failure (HF) progression. Pathological remodeling of the central nervous system represents a plausible upstream event associated with central sympathetic hyperactivity, whereas dysfunction of the brain–heart axis may act as a pivotal hub involved in this pathological process. This review systematically summarizes the functional characteristics of major sympathetic regulatory nuclei under HF, including the subfornical organ (SFO), paraventricular nucleus of the hypothalamus (PVN), rostral ventrolateral medulla (RVLM), and nucleus tractus solitarius (NTS). Following the pathological logic from upstream initiation to inter-organ closed-loop responses, seven interconnected pathological mechanisms are analyzed: glial cell activation and neuroinflammation, endoplasmic reticulum stress, renin–angiotensin system (RAS) imbalance, abnormal signaling pathways and transcription factors, impaired neuronal microenvironment homeostasis, dysregulated post-transcriptional and post-translational modifications, and extracellular vesicle-mediated inter-organ signal transmission. Their cross-regulation and positive feedback amplification effects are highlighted. Multidimensional central-targeted intervention strategies established on this basis possess important fundamental significance and translational potential. This review also discusses current scientific challenges and prospects for interdisciplinary frontiers, providing theoretical references and practical insights for central regulation research in HF and its precise clinical translation.