p53 inhibitor(Astex Pharmaceuticals/MSD)

Lipid metabolism disorders have been confirmed to be closely related to kidney injury caused by adriamycin (ADR) and obesity, respectively. However, it has not been explored whether lipid metabolism disorders appear progressively more severe after ADR-based chemotherapy in the obese state, and the specific molecular mechanism needs to be further clarified.

This study was designed to examine the role of p53-fibroblast growth factor 21 (FGF21) axis in ADR-induced renal injury aggravated by high-fat diet (HFD).

We engineered Fgf21 KO mice and used long-term (4 months) and short-term (0.5 months) HFD feeding, and ADR-injected mice, as well as STZ-induced type 1 diabetic mice and type 2 (db/db) diabetic mice to produce an in vivo model of nephrotoxicity. The specific effects of p53/FGF21 on the regulation of lipid metabolism disorders and its downstream mediators in kidney were subsequently elucidated using a combination of functional and pathological analysis, RNA-sequencing, molecular biology, and in vitro approaches.

Long-term HFD feeding mice exhibited compromised effects of FGF21 on alleviation of renal dysfunction and lipid accumulation following ADR administration. However, these impairments were reversed by p53 inhibitor (pifithrin-α, PFT-α). PFT-α sensitized FGF21 actions in kidney tissues, while knockout of Fgf21 impaired the protective effects of PFT-α on lipid metabolism. Mechanistically, p53 impaired the renal expression of FGF receptor-1 (FGFR1) and thereby developed gradually into FGF21 resistance via inhibiting hepatocyte nuclear factor 4 alpha (HNF4α)-mediated transcriptional activation of Fgfr1. More importantly, exogenous supplementation of FGF21 or PFT-α could not only alleviate ADR-induced lipid metabolism disorder aggravated by HFD, but also reduce lipid accumulation caused by diabetic nephropathy.

Given the difficulties in developing the long-acting recombinant FGF21 analogs for therapeutic applications, sensitizing obesity-impaired FGF21 actions by suppression of p53 might be a therapeutic strategy for maintaining renal metabolic homeostasis during chemotherapy.

Bisphenol AF (BPAF), one of the most common bisphenol analogues, has been reported to exhibit higher estrogenic activity compared to bisphenol A (BPA) due to the presence of additional hydrophobic groups. To comprehensively understand the male reproductive toxicity of BPAF, TM3 Leydig cells were used to investigate the effects of BPAF on cell proliferation, apoptosis, and cell cycle arrest. The underlying mechanisms of cellular responses induced by BPAF were examined through analysis of target mRNA and protein expression. Results showed that BPAF treatment reduced cell viability and induced both G2/M cell cycle arrest and apoptosis in a time- and dose-dependent manner in TM3 Leydig cells. RNA sequencing analysis and experimental verification further revealed that the p53 signaling pathway was involved in BPAF-induced cytotoxicity. Furthermore, Pifithrin-α (PFT-α), a p53 inhibitor, attenuated BPAF-induced G2/M cell cycle arrest and apoptosis. These results demonstrate that the p53 signaling pathway mediates BPAF-induced cell cycle arrest and apoptosis in Leydig cells, providing mechanistic insights into BPAF's toxicological effects on the male reproductive system.