Podocyte injury in LN displays significant pathological diversity across different disease classes (30). In proliferative LN (classes III/IV), anti-dsDNA antibodies activate complement pathways and induce endothelial inflammation, while subendothelial immune complex (IC) accumulation leads to structural alterations in podocytes (6, 31). These changes include cytoskeletal reorganization through reduced nephrin expression and inhibited VEGF-A signaling (32). Conversely, class V membranous LN primarily involves subepithelial IC deposition, which stimulates localized complement activation and functional impairment of podocytes (33). This manifests as foot process effacement without basement membrane disruption, differing mechanistically from the structural damage (podocyte detachment, basement membrane rupture) seen in proliferative forms. These distinctions may account for the more favorable long-term outcomes observed in class V disease (34). Emerging evidence indicates that the extent of glomerular endothelial damage in proliferative LN positively associates with foot process width (FPW). Furthermore, IgG antibodies promote podocyte cytoskeletal reorganization by activating β1-integrin-dependent pathways (32). Dysregulation of the VEGF-endothelin axis also contributes to filtration barrier dysfunction through increased proinflammatory mediator release and impaired podocyte–endothelial crosstalk (35). Interestingly, while VEGF-A downregulation in proliferative LN contributes to endothelial injury and proteinuria, class V membranous LN often shows preserved or even upregulated VEGF-A levels, potentially reflecting a compensatory response to subepithelial immune complex deposition (36, 37). These subtype-specific differences underscore a knowledge gap in understanding VEGF signaling dynamics and highlight the need for tailored therapeutic strategies targeting angiogenic pathways.

Studies on podocyte-linked biomarkers in LN highlight their dual function as both immune complex-mediated injury targets and disease progression markers. The reduced expression of podocyte-specific proteins in glomeruli emphasizes the critical role of cytoskeletal disruption in LN glomerulopathy pathogenesis (50). Furthermore, urinary sediment analysis in active LN patients detects abnormal levels of podocalyxin, synaptopodin mRNA, and immature nephrin/GLEPP1 proteins, supporting their use as noninvasive diagnostic tools for glomerular damage (51). Proteomic analyses have identified α-enolase and annexin A1 as podocyte-targeted autoantigens in LN, where their strong interaction with glomerular IgG suggests involvement in immune complex formation (52, 53). Podocyte-derived microparticles (MPs), carrying surface markers like annexin V and podocalyxin, serve as dynamic indicators of renal disease activity and histopathological changes in SLE (54). Importantly, NF-κB signaling is consistently implicated in proinflammatory gene expression in LN podocytes, driving production of cytokines and apoptotic markers (55). Besides, the NF-κB pathway also orchestrates cell survival and tissue repair mechanisms. For instance, selective inhibition of canonical NF-κB mitigates glomerular inflammation, while blockade of noncanonical branches could disrupt podocyte adaptation and regeneration (29, 56). Future studies need to clarify which subunits and downstream effectors of NF-κB signaling represent optimal therapeutic windows in LN (57). The extent of podocyte injury closely parallels proteinuria severity, as research shows that foot process effacement (FPE) in both proliferative and non-proliferative LN correlates with significant protein loss, alongside diminished expression of mature podocyte markers like synaptopodin, nephrin, and GLEPP1 in proliferative forms (34). Additionally, these injured podocytes exacerbate LN-related inflammation by releasing cytokines such as IL-1β, TNF-α, IFN-α, and IFN-γ, which sustain renal damage (58). Osteopontin (OPN), produced by T cells, enhances macrophage recruitment into glomeruli (59) and may also modulate podocyte signaling and movement, thereby contributing to proteinuria onset and progression (60).

Immunosuppressive drugs exhibit podocyte-preserving properties in LN by modulating slit diaphragm components. Glucocorticoids reinforce the actin cytoskeleton, stimulate RhoA/ROCK pathways, and enhance nephrin synthesis, recovering podocin immunofluorescence to 82% of baseline in NZB/W mice (72). Cyclophosphamide diminishes podocyte apoptosis by inhibiting IL-6/JAK2/STAT3 cascades, with combination therapies increasing nephrin-podocin colocalization by 2.3-fold (72). Calcineurin inhibitors (cyclosporine A, tacrolimus) attenuate foot process effacement by obstructing NFAT signaling and facilitating podocin reintegration into slit diaphragms, thus restoring glomerular charge selectivity (73).

Belimumab, a humanized IgG1λ monoclonal antibody, neutralizes soluble BAFF to prevent BAFFR/BCMA/TACI receptors and curtailing pathogenic B-cell expansion and autoantibody generation (74–78). The landmark BLISS-LN phase III trial revealed that belimumab adjunctive therapy significantly enhanced primary and complete renal responses at 104 weeks compared to standard care alone, with a safety profile matching placebo (79, 80). However, the trial’s findings must be interpreted with caution, as its relatively short follow-up duration and underrepresentation of patients with severe proteinuria or class V LN limit generalizability. Efficacy was more pronounced in patients on mycophenolate mofetil (MMF) induction, possibly due to baseline disease heterogeneity (79, 81). While proliferative LN with mild proteinuria showed 9–10% improvements in PERR/CRR, membranous LN or high-proteinuria subgroups derived no significant benefit (82). East Asian populations confirmed its robust efficacy, demonstrating a 63% reduction in renal risk (83), culminating in its 2019 FDA approval as the first SLE-specific biologic.

Telitacicept simultaneously inhibits BAFF and APRIL, disrupting their binding to BCMA/TACI and impairing long-lived plasma cell survival and B-cell hyperactivity (84). A retrospective analysis of 72 active SLE patients (34 with LN) reported median reductions of 77% in 24-hour proteinuria and 75% in anti-dsDNA titers at 24 weeks, with PRR and CRR rates of 76.24% and 70.58%, respectively. By 52 weeks, CRR reached 66.67% (6/9), with infections being the most frequent adverse event (23.6%) (85). Following global phase III trial approvals (NMPA/EMA), large-scale efficacy validation is underway. In refractory LN, sequential telitacicept-rituximab therapy achieved 100% CRR at 19 months, surpassing belimumab monotherapy without increased infection risk (15), suggesting superior efficacy in treatment-resistant cases pending further verification. Rituximab is a chimeric anti-CD20 IgG1κ antibody that depletes CD20⁺ B cells through ADCC and CDC mechanisms while dampening T-cell-driven autoimmunity (86, 87). The LUNAR phase III trial did not meet its primary endpoint, with no significant renal response improvement at 52 weeks in class III/IV LN, potentially due to CDC impairment in hypocomplementemic states and BAFF rebound (88–90). Nevertheless, refractory LN cohorts demonstrate clinical utility: a meta-analysis of 300 patients revealed a 74% overall response rate, with superior outcomes in class III LN (91, 92). Prospective studies corroborate its glucocorticoid-sparing effects and acceptable safety (93), leading to its classification as a second-line refractory LN therapy in the 2024 KDIGO guidelines (94).

The proteasome inhibitor bortezomib induces plasma cell apoptosis via endoplasmic reticulum stress and NF-κB pathway inhibition. In NZB/W F1 mice, bortezomib significantly depleted splenic and bone marrow-resident long-lived plasma cells (95–97). A Japanese multicenter randomized controlled trial in refractory SLE reported a 75% SLE Responder Index at 12 weeks, compared to 40% in placebo, despite similar anti-dsDNA levels at 24 weeks (98). In China, five patients with high-activity LN showed partial renal response after four cycles, with 60% achieving complete renal response (CRR) and 20% progressing to end-stage renal disease over three years (99). Another Spanish retrospective study found that bortezomib reduced median SLEDAI from 27 to 0, with CRR and PRR rates of 8.3% and 83.3%, respectively, though hypogammaglobulinemia (IgG <500 mg/dL) occurred in 50% of patients (100). However, the immunosuppressive side effects of bortezomib require serious attention, with infection being the most frequently observed adverse event (101). These safety concerns, combined with small sample sizes and limited follow-up constrain conclusions regarding long-term efficacy and safety (98–100). Alternatively, daratumumab, a CD38-targeting IgGκ monoclonal antibody, depletes >90% of CD38⁺plasma cells via antibody-dependent cellular cytotoxicity (ADCC) in bone marrow and inflamed tissues (97, 102, 103). In Germany, two refractory LN cases treated with daratumumab-belimumab showed a 50% reduction in anti-dsDNA antibodies and a 62 ± 8% decline in interferon signature gene expression by week 12, with no severe adverse events (102). Similarly, an Italian cohort of six refractory LN patients demonstrated a 66% reduction in SLEDAI, 86% decrease in proteinuria, 35% improvement in serum creatinine, and 1.8-fold rise in C4 after 12 months (104). Daratumumab demonstrates comparable autoantibody clearance efficacy to bortezomib with a trend toward lower infectious adverse events (98, 104, 105), supporting its therapeutic promise in refractory LN.

Macrophages, as a major subset of innate immune cells, represent the predominant infiltrating cell population in the kidneys of LN patients. Compounds targeting macrophage polarization include total glucosides of paeony, which upregulate PD-L2 expression via STAT6 phosphorylation, inducing M2-like macrophage polarization and exerting immunosuppressive effects to attenuate glomerular damage in LN mice (106). Dihydroartemisinin (DHA), a metabolite of artemisinin with potent antimalarial properties, also demonstrates remarkable anti-inflammatory and immunomodulatory activities. By inhibiting ITK signaling to suppress T follicular helper (Tfh) cells and reducing serum levels of IgG, IgM, IgA and anti-dsDNA antibodies, DHA significantly alleviates LN symptoms (107). Genetically engineered macrophage membranes overexpressing CCR2 can enhance the targeted delivery of DHA-loaded nanoparticles to inflammatory sites in LN, thereby reducing monocyte/macrophage infiltration and reprogramming the M1/M2 macrophage balance to modulate the renal immune microenvironment and ameliorate kidney injury (108). Artesunate, a semi-synthetic derivative of artemisinin, improves lupus nephritis symptoms by regulating the T follicular regulatory to T follicular helper cell ratio and activating the JAK2-STAT3 signaling pathway, consequently decreasing renal anti-dsDNA antibody deposition and reducing pathogenic cytokine levels including IL-6, IFN-γ, and IL-21 (109). Furthermore, LLDT-8, a novel triptolide analog, has been demonstrated by ZHANG et al. (28) to exhibit therapeutic effects against LN through suppressing chemokine and IL-6 expression, decreasing renal macrophage and neutrophil infiltration, and reducing glomerular IgG deposition in LN mice (110).