Hyperlipidemia and associated cardiovascular diseases (CVDs) represent a substantial and escalating global health burden, significantly contributing to worldwide mortality (Zhong et al., 2019). Postmenopausal women exhibit a significantly heightened susceptibility to hyperlipidemia caused by estrogen deficiency (Lobo and Gompel, 2022). This condition, characterized by elevated levels of triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C), constitutes a substantial risk factor for CVD. Epidemiological data have confirmed the high prevalence of hyperlipidemia, with longitudinal cohort studies indicating that 78.4% of postmenopausal women develop this lipid disorder, while cross-sectional data demonstrate that its prevalence is significantly higher in this demographic than in premenopausal counterparts (Jeong et al., 2022; Xi et al., 2020). Effective management of postmenopausal hyperlipidemia is fundamental for mitigating CVD risk. However, current interventions for postmenopausal hyperlipidemia show limited efficacy, and the underlying mechanisms remain poorly understood. While statins are the foundation of lipid-lowering therapy, their clinical utility in postmenopausal women is restricted, given their association with an increased risk of incident diabetes compared with that observed in men (Kao et al., 2024). Moreover, although hormone replacement therapy (HRT) effectively counteracts estrogen deficiency, its long-term use has a well-established link with breast and endometrial cancers, which limits its application (Grossman et al., 2017; Rodriguez et al., 2020; Wang et al., 2018). These challenges highlight the urgent need for effective, estrogen receptor-independent strategies for the management of hyperlipidemia in this population. Recent research indicates that endoplasmic reticulum stress (ERS) is markedly elevated in the postmenopausal state, playing a crucial role in the pathogenesis of hyperlipidemia and associated metabolic disorders (Li et al., 2020; Singh et al., 2020). Consequently, this ERS-driven lipid metabolic dysregulation represents a promising therapeutic focus for interventions targeting postmenopausal hyperlipidemia.

ERS and lipid dysregulation are closely interrelated. ERS promotes hepatic lipid accumulation by enhancing lipogenesis, impairing fatty acid oxidation, and reducing VLDL secretion (Kim, 2024; Ma et al., 2019; Xiong et al., 2014). Meanwhile, lipid excess directly induces or exacerbates ERS, establishing a self-perpetuating pathogenic cycle. Cyclooxygenase 2 (COX-2) upregulation in postmenopausal women greatly contributes to the pathogenesis of hormone-responsive breast cancer and osteoporosis (Bowers et al., 2015; Gao et al., 2024). Estrogen deficiency heightens the responsiveness of COX-2 to dietary lipids, driving its pathogenic overactivation in postmenopausal metabolic disorders (Li et al., 2020). Notably, COX-2 activation has been linked to the induction of ERS, notably through the upregulation of glucose regulatory protein 78 (GRP78), a key chaperone whose elevated expression serves as a biomarker of ERS (Chen et al., 2024). GRP78 expression, is consistently upregulated observed in hepatic lipid metabolism disorders. Consequently, the COX-2/GRP78 pathway constitutes a plausible mechanistic link connecting estrogen deficiency, ERS, and the onset of postmenopausal hyperlipidemia.

Paeonol (Pae, 2′-hydroxy-4′-methoxyacetophenone), a bioactive constituent of the root of Paeonia suffruticosa, exhibits a broad spectrum of pharmacological activities. Studies have demonstrated its efficacy in alleviating disorders associated with estrogen deficiency, particularly osteoporosis and neuropsychiatric symptoms (Kang et al., 2024; Tsai et al., 2008). Notably, Pae exhibits inhibitory effects against breast and ovarian cancer, as well as preventive effects against CVD (Liang et al., 2024; Saahene et al., 2018; Yang et al., 2025). These findings suggest that Pae has potential as an effective agent for preventing postmenopausal hyperlipidemia. Nevertheless, the precise underlying mechanisms and regulatory targets require further investigation.

Although ERS has been implicated in metabolic dysregulation, whether the COX-2/GRP78-mediated ERS pathway is involved in postmenopausal hyperlipidemia remains undefined. Given the risks associated with estrogen receptor-dependent mechanisms in HRT, there is an urgent need for safer, estrogen receptor-independent alternatives. Pae, displays a favorable safety profile and has shown potential as an estrogen receptor-independent agent for the management of menopausal comorbidities (Kang et al., 2024; Liu et al., 2024). However, whether Pae exerts regulatory effects on the COX-2/GRP78-mediated ERS pathway in postmenopausal hyperlipidemia remains unexplored. Here, we hypothesized that Pae alleviates postmenopausal hyperlipidemia by targeting this pathway independently of estrogen receptor signaling. Through integrated approaches, we identified COX-2 as a direct target of Pae. Additionally, we demonstrated that Pae exerts lipid-lowering effects, an effect mediated via the suppression of the COX-2/GRP78-dependent ERS pathway, thereby offering a novel and safer therapeutic strategy for postmenopausal hyperlipidemia.