TGF-β/Smad3 signaling is a key pathway leading to the cell death and renal fibrosis. Here we report a new mechanism through which Smad3 mediates renal fibrosis by downregulating the glutathione peroxidase 4 (GPX4), a central inhibitor for ferroptosis. In patients with chronic kidney disease (CKD) and a mouse model of unilateral ureteral obstruction (UUO), progressive renal fibrosis was associated with the overactive Smad3 signaling and the development of ferroptosis identified by decreased GPX4 while increasing two ferroptosis biomarkers including the Transferrin receptor 1 (TFR1) and 4-Hydroxynonenal (4-HNE). Mechanistically, we uncovered that Smad3 could bind directly to GPX4 to repress its transcription while increasing TFR1 and 4-HNE expression, which was abolished when this binding site was mutated. This novel finding was functionally confirmed in the UUO mice and mouse embryonic fibroblasts (MEFs) in which deletion of Smad3 protected against UUO and transforming growth factor-β1 (TGF-β1)-induced loss of GPX4, upregulation of TFR1 and 4-HNE, and progressive renal fibrosis in vivo and in vitro. Importantly, we also found that GPX4 was a downstream target gene of Smad3 and functioned to protect against Smad3-mediated renal fibrosis as silencing GPX4 restored UUO-induced severe renal fibrosis in Smad3 KO mice and in TGF-β1-stimulated Smad3 KO MEFs and SIS3-treated HK-2 cells. Thus, GPX4 is protective in renal fibrosis. Smad3 mediates renal fibrosis via a mechanism associated with GPX4-dependent ferroptosis. The protective effect of GPX4 on Smad3-mediated renal pathologies suggests that targeting the Smad3/GPX4 axis may be a novel therapy for CKD.

Background and purpose: Renal fibrosis is a common characteristic of chronic kidney disease (CKD). Studies have confirmed the role of ferroptosis in the pathogenesis of various kidney diseases, making it a new research hotspot in the field of renal fibrosis. Monomers of Chinese herbal medicines (CHMs) can improve renal fibrosis by multi-target inhibition of ferroptosis. This review aimed to explore the roles and mechanisms of CHMs in renal fibrosis.Methods: Using the keywords “ferroptosis”, “chronic kidney disease”, “renal fibrosis”, “Chinese herbal medicine”, “natural products”, “bioactive components”, and “herb”, we conducted an extensive literature search of several databases, including PubMed, Web of Science, CNKI, and Wanfang database, to identify studies reporting the role of CHM monomers in inhibiting ferroptosis and improving renal fibrosis. The names of the plants covered in the review have been checked through MPNS (http://mpns.kew.org). All monomers of CHMs were identified in the Pharmacopoeia of the People’s Republic of China.Results: In total, 21 monomers of CHMs were identified in this study, most of which were flavonoids, followed by terpenoids and coumarins. This review showed that monomers of CHMs inhibited ferroptosis and improved renal fibrosis through multi-target mechanisms. They maintained iron homeostasis by acting on NCOA4 and Nrf2 to reduce ferritinophagy. They also inhibited lipid peroxidation and regulated the antioxidant system by modulating ACSL4, NOX4, Nrf2, FSP1, and GPX4 and inhibiting Smad3 to improve renal fibrosis.Conclusion: Monomers of CHMs effectively inhibited ferroptosis and prevented renal fibrosis in various animal models and cell models of CKD. However, further in-depth studies with better designs are needed to identify the exact targets of monomers of CHMs and improve the treatment of renal fibrosis and CKD.

Background: Chronic kidney disease (CKD), a global health challenge, is closely linked to renal fibrosis progression. Copper, an essential trace element, influences cellular functions, yet its role in CKD-related fibrosis remains unclear. This study explores the causal relationship between serum copper levels and renal fibrosis in CKD.Methods: A two-sample Mendelian Randomization (MR) analysis integrated GWAS and FinnGen data. Serum copper and other metals were quantified via ICP-MS in 505 CKD patients and 50 controls. Renal fibrosis was histologically assessed in 168 biopsy-confirmed cases. Multivariable logistic regression and restricted cubic splines (RCS) evaluated associations between copper levels, renal function, and fibrosis severity, adjusting for demographics and biochemical parameters.Results: MR confirmed causality between elevated copper and CKD risk. CKD patients had higher serum copper than controls (957.10 ± 273.82 vs. 795.50 ± 143.85 ng/ml, p < 0.001), with progressive increases from stage 1 to 5 (p < 0.001). In biopsy-proven cases, severe fibrosis (>5%) correlated with higher copper levels and lower eGFR versus mild fibrosis (≤5%). Adjusted analysis identified quartile 4 copper levels (>961.64 ng/ml) as an independent predictor of severe fibrosis (OR = 2.75, 95% CI: 1.06–7.16, p < 0.001). RCS revealed non-linear relationships between copper, fibrosis (P for non-linear = 0.038), and eGFR (P for non-linear = 0.005).Conclusion: Elevated serum copper is independently associated with renal fibrosis in CKD, suggesting copper dysregulation may contribute to fibrotic pathogenesis. These findings underscore the therapeutic potential of targeting copper metabolism to mitigate CKD progression.

IgA nephropathy has a poor prognosis. This network meta-analysis aims to evaluate the efficacy and safety of all currently available drugs comprehensively and systematically for the treatment of IgA nephropathy. We searched MEDLINE, EMBASE, Cochrane Library until Nov 15, 2024. Primary outcomes were 24-hour proteinuria and UPCR; secondary included ESRD, doubling serum creatinine (SCr), and adverse events (AEs). Bayesian analysis provided RRs and SUCRA rankings. Analyzing 37 RCTs (4889 patients) with 15 interventions: For reducing 24-hour proteinuria, AZA+CTX ranked highest (SUCRA 95.8%), superior to systemic corticosteroids (45.2%), other immunosuppressants (CsA 82.1%, MMF 72.1%, AZA 43.9%, CTX 21.0%), BAFF/APRIL inhibitors (63.6%), HCQ (62.9%), and RASi (16.4%). For UPCR reduction, BAFF/APRIL inhibitors (91.3%) and ERA (74.2%) outperformed systemic corticosteroids (46.8%), other immunosuppressants (MMF 74.0%, AZA+CTX 68.2%, TAC 43.8%), and TRF-budesonide (65.5%). Regarding renal protection, LEF (doubling SCr: 92.6%; ESRD: 79.1%) and systemic corticosteroids (doubling SCr: 77.0%; ESRD: 72.6%) were effective for both endpoints. For ESRD risk reduction, SGLT2i ranked second (77.0%), followed by TRF-budesonide (58.4%), with AZA+CTX being least favorable (5.5%). Safety analysis showed higher AE/SAE risks with CTX/AZA+CTX; TRF-budesonide had the next highest SAE ranks, though inter-group differences were non-significant. AZA+CTX was associated with an effective reduction in 24-hour proteinuria in small RCTs, but it also increased the risk of renal failure progression and had poor safety. Systemic corticosteroids and TRF-budesonide balanced proteinuria reduction with slowing renal failure, though SAE vigilance is needed. Among new agents, BAFF/APRIL inhibitors and ERA excelled at UPCR reduction with favorable safety. In supportive care, SGLT2i significantly reduced CKD progression risk while maintaining a favorable safety profile. CRD42024582600 The online version contains supplementary material available at 10.1186/s12882-026-04848-7.