Targeting Macrophage Glycolytic-Serine Metabolism and NF-κB Activation by Compound Xiancao Granule Confers Renoprotection in Diabetic Nephropathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Xiancao Granule (FFXCKL), a traditional Zhuang medicinal formula, has long been used for diabetic complications, yet its molecular mechanism against diabetic nephropathy (DN) remains incompletely understood.

AIM OF THE STUDY: To investigate whether FFXCKL alleviates DN by modulating macrophage glucose-serine metabolism and NF-κB-mediated inflammatory responses.

MATERIALS AND

METHODS

db/db mice and high-glucose-stimulated RAW264.7 macrophages were treated with FFXCKL. Renal function, histopathology, inflammatory cytokines, macrophage polarization, metabolomic profiles, transcriptomic alterations, and the expression of key glycolytic, serine biosynthetic, and NF-κB signaling molecules were evaluated. Glycolytic (2-deoxy-D-glucose) and serine synthesis inhibitors (NCT-503), together with NF-κB activator and inhibitor (JSH-23), were used to investigate the underlying mechanism.

RESULTS

FFXCKL improved hyperglycemia, proteinuria, renal dysfunction, and histopathological injury while reducing fibrosis and systemic inflammation in db/db mice. It suppressed high-glucose-induced M1 macrophage polarization and normalized alterations in glucose and serine metabolism, accompanied by downregulation of HK-2, PKM2, PHGDH, PSAT1, and PSPH. Transcriptomic analysis identified NF-κB signaling as a major pathway affected by FFXCKL, and pharmacological modulation of NF-κB supported its involvement in regulating macrophage inflammatory and metabolic responses. Major limitations include the absence of isotope-tracing metabolic flux analysis and macrophage-specific genetic validation of the proposed mechanism.

CONCLUSIONS

FFXCKL attenuated diabetic nephropathy by suppressing macrophage-associated inflammatory responses and improving glucose-serine metabolic disturbances, with effects associated with inhibition of NF-κB signaling. These findings support FFXCKL as a promising multi-target immunometabolic therapeutic strategy for diabetic nephropathy while warranting further mechanistic validation.