p53 inhibitor(Astex Pharmaceuticals/MSD)

Acute lung injury (ALI) is a condition with acute respiratory failure caused by various factors, characterized by severe hypoxemia and diffuse alveolar damage, involving multiple cytokines and signaling pathways. This study investigates the role of secreted phosphoprotein 1 (SPP1) in ALI and explores its underlying mechanisms through a series of in vitro and in vivo experiments. Our results demonstrate that SPP1 expression is significantly upregulated in ALI animal models, correlating with increased oxidative stress and inflammatory responses. In LPS‐induced lung injury models, elevated levels of malondialdehyde (MDA) and IL1β, along with decreased superoxide dismutase (SOD) levels, were observed, further confirming the active state of SPP1 in ALI. In vitro experiments using BEAS‐2B cells revealed that LPS treatment increased IL1β and reactive oxygen species (ROS) levels while decreasing SOD levels, with concomitant upregulation of SPP1. SPP1 knockdown significantly inhibited these changes, directly confirming its regulatory role in ALI progression. We further explored the regulatory mechanisms of SPP1 on the senescence‐associated secretory phenotype (SASP), a key pathological process in ALI. SA‐β‐GAL staining and γ‐H2AX results indicated elevated cellular senescence in LPS‐treated cells and ALI models. SPP1 knockdown reduced senescence markers, enhanced cell viability, decreased apoptosis, and improved cell proliferation capacity, suggesting that SPP1 promotes ALI via the SASP phenotype. Mechanistically, we found that SPP1 regulates ALI via the p53 signaling pathway. LPS treatment increased p‐p53 levels, whereas SPP1 knockdown reduced p53 activation. The use of a p53 inhibitor further suppressed SASP and improved ALI‐related indicators. Animal model validation corroborated these findings, showing that SPP1 knockdown and p53 inhibitor treatment reduced lung tissue damage and improved ALI‐related indicators. Collectively, our study reveals a novel mechanism by which SPP1 regulates ALI progression via the p53 signaling pathway and SASP. This discovery not only enriches our understanding of ALI pathogenesis but also provides a new therapeutic target and potential intervention strategies for ALI treatment.

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.