Lupus nephritis (LN) is one of the most common and severe complications of systemic lupus erythematosus (SLE). Approximately 40 %–60 % of SLE patients develop LN, and up to 10 % of these cases may progress to renal failure (Gatto et al., 2025; Mohan et al., 2023). The pathogenesis of LN begins with the deposition of immune complexes in the kidney, which activates the complement system, recruits numerous immune cells, and triggers intense inflammatory responses, thereby disrupting the homeostasis of the renal microenvironment (Mohan et al., 2023). The extracellular matrix (ECM) constitutes a major component of the renal immune microenvironment. Beyond anchoring renal cells, it also regulates cellular functions through receptors such as integrins, maintains tissue homeostasis, and ensures normal kidney filtration (Di et al., 2025; Li et al., 2022; Rayego-Mateos et al., 2021). In LN, persistent inflammation and injured renal cells lead to excessive ECM production, disrupting the balance between synthesis and degradation. This results in aberrant ECM accumulation, which replaces normal kidney structures and ultimately promotes renal fibrosis. Renal fibrosis represents the final common pathway through which LN progresses to end-stage renal disease (Di et al., 2025). Therefore, restoring the balance between ECM production and degradation is crucial for controlling LN progression.

Fibroblast activation and epithelial-mesenchymal transition (EMT) play a central and common role in initiating pathological extracellular matrix (ECM) deposition in renal (Livingston et al., 2023; Rayego-Mateos et al., 2021). Under physiological conditions, fibroblasts regulate ECM synthesis and maintenance, thereby preserving tissue architecture and homeostasis—a process that is essential and beneficial for mild tissue repair. However, in cases of severe or chronic tissue injury, fibroblasts become activated and express α-smooth muscle actin (α-SMA), differentiating into myofibroblasts. These cells exhibit enhanced proliferative capacity and produce excessive ECM components, disrupting metabolic equilibrium and leading to aberrant ECM accumulation (Rayego-Mateos et al., 2021). It is worth noting that the cellular origins of myofibroblasts remain debated; however, recent studies suggest that they primarily derive from resident fibroblasts and pericytes (Huang et al., 2023; Kuppe et al., 2021; Yamashita and Kramann, 2024). Although fibroblast activation has been shown to be induced by multiple factors—such as TGF-β1, FGF2, WNT, and tenascin C—there remains a lack of effective therapeutic agents capable of specifically targeting this process (Cohen et al., 2024; Livingston et al., 2023; Xie et al., 2022).

Zhen-Wu-Tang (ZWT) is a classic traditional Chinese formula widely recognized for its therapeutic effects in chronic kidney diseases, such as type 2 cardiorenal syndrome (Xu et al., 2024), membranous nephropathy (Liu et al., 2019), and nephrotic syndrome (Lao et al., 2025; C.-L. Liang et al., 2019). Furthermore, clinical studies have demonstrated that combining ZWT with immunosuppressive agents leads to improved outcomes in patients with LN (Bao-lin et al., 2019). Our recent study also revealed that ZWT attenuates renal injury in LN by inhibiting the IL-15/STAT3 signaling pathway, thereby reducing kidney-resident CD8+ memory T cells (Liang et al., 2024). While immunomodulation is essential for controlling autoimmunity in Lupus Nephritis (LN), progressive renal failure is ultimately driven by often irreversible interstitial fibrosis. Chronic inflammation establishes a pro-fibrotic milieu that directly activates fibroblasts. Therefore, directly targeting this fibrotic cascade represents a critical therapeutic paradigm shift. Notably, ZWT has demonstrated promising anti-fibrotic efficacy in preclinical models, suggesting its potential for such a strategy. In the context of myocardial fibrosis, ZWT mitigates fibrosis by inhibiting TLR4/NF-κB-mediated M1 macrophage polarization (Fang et al., 2024). Conversely, for renal fibrosis, ZWT promotes mitochondrial bioenergetics via NRF2/TFAM activation and modulates Wnt4/β-catenin signaling (La et al., 2018; Zheng et al., 2023). Further investigation reveals that NRF2 and PI3K/Akt activation provide protection against cisplatin-induced acute kidney injury (Liu et al., 2017). However, it remains unclear whether ZWT can ameliorate fibrosis in lupus nephritis (LN) and the underlying mechanisms warrant further investigation.

In this study, we demonstrated that ZWT ameliorates the progression of LN toward renal fibrosis. Our results indicate that ZWT suppresses fibroblast activation and significantly reduces the deposition of ECM in the kidney. Importantly, we found that this protective effect is associated with the modulation of multiple signaling pathways, including the PI3K pathway (PI3K/AKT), the NF-κB pathway (IκBα/p65), the TGF-β pathway (SMAD2/3), and the JAK–STAT pathway (JAK2/STAT3). These findings suggest that ZWT could represent a promising therapeutic strategy for mitigating the progression of LN.