Fig 1: Network pharmacology analysis and validation of TP53 as a candidate target associated with the effect of nobiletin in diabetic nephropathy. (A) Venn diagram showing overlapping targets between diabetic nephropathy (DN) and NOB; (B) protein-protein interaction (PPI) network highlighting TP53 as a central hub; (C,D) surface plasmon resonance (SPR) sensorgrams and binding curves showing interaction between NOB and TP53 (KD = 7,157 nM); (E) Gene Ontology (GO) enrichment of overlapping targets; (F) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis; (G) immunofluorescence staining of TFEB (green) and TP53 (red) in renal tissue from control, model, and NOB-H groups. Nuclei are stained with DAPI (blue). These data show that reduced TP53 signal after NOB treatment was accompanied by increased TFEB expression/nuclear localization, but they do not prove direct transcriptional regulation of TFEB by TP53 (400 ×). Renal TP53/TFEB immunofluorescence was performed in n = 3 animals per group. The KD of 7.157 μM indicates moderate micromolar affinity and supports a measurable interaction under the SPR assay conditions without establishing potent inhibition or in vivo target engagement.
Fig 2: Nobiletin modulates pyroptosis-, apoptosis-, and necroptosis-related mRNA expression in the kidneys of db/db mice. (A–F) Apoptosis-related genes (TP53, CASPASE3, BAX, BCL-2, CASPASE8, and CASPASE9); (G–L) pyroptosis-related genes (GSDMD, AIM2, NLRP3, ASC, CASPASE1, and IL-1β); (M–R) necroptosis-related genes (TNF, IL-17, RIPK1, RIPK3, ZBP1, and MLKL). Data are presented as mean ± SEM (n = 5 per group), and statistical significance was determined by one-way ANOVA followed by Tukey’s post-hoc test or an appropriate alternative test (P < 0.05). Exact two-sided P-values are displayed above the corresponding comparison brackets, and each bracket identifies the groups compared.
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