Obesity (OB) and atherosclerosis (AS) represent two major interconnected health crises that collectively impose a substantial burden on global healthcare systems. The pathological essence of OB extends beyond mere body weight, defined as a recalcitrant metabolic disorder marked by aberrant adipocyte expansion and dysfunctional fat distribution. Recognized as a serious multifactorial disease by professional societies, OB acts as a primary catalyst for a spectrum of chronic conditions(Jastreboff et al., 2019). The epidemiological landscape in China, as outlined in a recent national report, reveals a concerning reality where the combined prevalence of overweight and OB affects more than 50 % of the adult population, underscoring its status as a paramount public health priority(The National Health Commission's bureau of disease prevention and control., 2020). The lethality of OB is often indirect, manifesting through its comorbidity with life-threatening diseases such as type 2 diabetes, cardiovascular disorders, and specific cancers, which consequently leads to a marked reduction in average life expectancy(Bray et al., 2018). It is evident that concomitant diseases caused by overweight or OB are strongly associated with the risk of death, a fact that is emphasized in different populations(Global et al., 2016). This firmly establishes the management of OB as a foundational strategy for broader disease prevention. Parallelly, AS stands as the principal pathological foundation for cardiovascular and cerebrovascular morbidity and mortality worldwide. A well-established body of evidence, including Mendelian randomization and clinical studies, has confirmed that OB is a major independent risk factor for AS and subsequent cerebrovascular diseases(Marini et al., 2020; Wu, Q. et al., 2025).Therefore, the prevention of AS in the obese population may reduce the risk of cardiovascular events.

The current therapeutic paradigm is shifting from weight-centric management to comprehensive cardiovascular risk reduction. Modern pharmacotherapy, particularly novel agents like the glucagon-like peptide-1 receptor agonist semaglutide, has demonstrated significant efficacy in weight loss and direct cardiovascular risk reduction. However, clinical challenges remain, including high cost, potential gastrointestinal side effects, and a limited impact on ameliorating systemic symptoms like fatigue and malaise in some patients(Celletti et al., 2025; Tuccinardi et al., 2025). While statin therapy remains a cornerstone for lipid control, its efficacy in reversing established plaques and alleviating related symptoms is limited, and it is associated with adverse effects such as hepatotoxicity, abnormal glucose metabolism, and myopathy(Zeng et al., 2025). Furthermore, the heterogeneity of obesity and the intricate interplay with AS pathogenesis necessitate therapeutic strategies beyond standardized protocols. A critical gap remains in developing interventions that simultaneously target the shared metabolic-inflammatory axis of OB-AS comorbidity and ameliorate systemic symptoms, thereby addressing the root of the disease continuum. This gap highlights the potential value of complementary, system-oriented strategies.

Traditional Chinese Medicine (TCM), with its holistic philosophy and emphasis on syndrome differentiation, offers a unique framework for managing complex metabolic disorders, and many clinical studies have shown that herbs are beneficial for weight loss(Forgerini et al., 2025). Its strength lies in multi-target regulation, potentially improving overall symptoms and quality of life, areas less focused on by conventional therapy. Within the TCM framework, the theory of “Spleen Deficiency” and “Phlegm-Dampness” provides a pivotal pathophysiological explanation for the OB-AS continuum. In modern medical terms, the TCM concept of the “spleen” broadly encompasses the digestive system's functions of transformation, transport, and nutrient absorption, while “phlegm-dampness” often refers to pathological metabolic accumulations or fluid disturbances. The ancient text Danxi Xinfa states, “Fat people have excessive phlegm and dampness,” conceptualizing dysfunctional “spleen” transportation as leading to the accumulation of pathological “phlegm-dampness.” This internal “dampness” can permeate the vessels, contributing to “blood stasis” and plaque formation. Consequently, fortifying the “spleen” and resolving “phlegm-dampness” is a core therapeutic principle. ShenLingBaiZhu Powder (SLBZP), a classic formula documented in Prescription of Peaceful Benevolent Dispensary, is the embodiment of this principle and a rational candidate for investigation. Comprising ten herbs, including Ginseng Root (Ren Shen), Indian Buead (Fu Ling), Largehead Atractylodes Rhizome (Bai Zhu), White Hyacinth Bean (Bai Bian Dou), Common Yam Rhizome (Shan Yao), Lotus Seed (Lian Zi), Villous Amomum Fruit (Sha Ren), Coix Seed (Yi Yi Ren), Balloonflower Root (Jie Geng), and Liquorice Root (Gan Cao), it is widely used for benefiting “qi” and strengthening the “spleen”, expelling “phlegm”, and resolving “dampness”.

The therapeutic potential of SLBZP for metabolic diseases is supported by a body of clinical and preclinical evidence(Fang and Wang, 2006; Huang and Lu, 2018; Shi et al., 2012; Wang, B. et al., 2017; Wang, 2013; Wang et al., 2017, Wang et al., 2017; Wu et al., 2022; Zhang, 2014; Zhang et al., 2018). Multiple clinical studies have demonstrated its efficacy in reducing body mass index and waist-to-hip ratio, improving glycolipid metabolism, and modulating adipokines and inflammatory markers in OB(Wang, B. et al., 2017; Wang et al., 2021; Wu et al., 2022); it also improves liver function, reverses hepatic steatosis, and ameliorates dyslipidemia in related conditions(Huang and Lu, 2018; Shi et al., 2012; Song et al., 2025; Wang, 2013; Zhang, 2014). Mechanistically, research indicates that SLBZP exerts its effects by modulating inflammation, lipid metabolism, and gut microbiota. For instance, it reduced body weight, improved hepatic steatosis and liver function, repaired the colonic mucosa, and improved the abundance of intestinal microbiota in high-fat diet-fed rats, which may be related to the down-regulation of the expression of serum endotoxin, TNF, interleukin-1β, and TLR4 pathway-related proteins(Zhang et al., 2018). It also increased hepatic and serum lipocalin levels, inhibited steroid regulatory element binding protein-1c expression, and regulated systemic lipid metabolism (Tang et al., 2020). In addition, a study conducted by Yang found that SLBZP can reduce the TNF and IL6 levels in the serum while also inhibiting TLR4 protein expression and activating p38 MAPK, resulting in improved lipid metabolism and reduced inflammation(Yang et al., 2014). Pan further found that SLBZP reduced body weight, fat mass, and visceral fat in high-fat diet-fed NAFLD model rats and suppressed the activation of inflammation and the expression level of interleukin-1 factor through the TLR4/NLRP3 signaling pathway(Pan et al., 2021). Collectively, this evidence, spanning theory, clinical efficacy, and molecular mechanism, positions SLBZP as a promising candidate for treating the OB-AS comorbidity, warranting a deeper investigation into its integrated mechanisms of action.

Therefore, to systematically decipher the integrated mechanism of SLBZP against OB and AS comorbidity, this study employs a multidisciplinary strategy. We utilized HPLC-Q-TOF-MS/MS, a powerful analytical technique ideal for profiling non-volatile organic compounds and metabolites(Zhong et al., 2009), to identify the bioactive constituents of SLBZP absorbed into the bloodstream. Concurrently, bioinformatic analysis was applied to mine high-throughput transcriptomic data to identify differentially expressed genes (DEGs) and elucidate the shared biological landscape of OB and AS(Orlov et al., 2021). By integrating these approaches through the lens of network pharmacology, which bridges TCM with systems biology and artificial intelligence(Zhao et al., 2023), we constructed a comprehensive “compound-target-pathway” network. This is followed by experimental validation in a relevant in vitro model of OB-AS crosstalk. This workflow aims to clarify the material basis and multi-target mechanisms of SLBZP in treating the interplay between OB and AS.