Increasing evidence indicates that phosphoserine phosphatase (PSPH) promotes tumorigenesis in certain types of cancer. However, its specific role and regulatory mechanism in bladder cancer (BCa) remain unknown. In this study, we found that the expression level of PSPH is significantly upregulated in BCa tissues and patients with high PSPH levels exhibited shorter survival rates. Depletion of PSPH inhibited cell growth and metastatic potential of BCa cells. In contrast, upregulated PSPH promoted BCa progression and resistance to GEM. Mechanistically, increased PSPH enhanced the promoter activity of S100A2 and promoted S100A2 expression which led to malignant progression of BCa. The transcription factor BACH1 bound to the promoter of PSPH and facilitated PSPH expression in BCa. In addition, we also found that Brusatol directly bound to BACH1 and promoted BACH1 degradation. This study demonstrates the oncogenic role of PSPH in BCa and reveals that PSPH, upregulated by BACH1, promoted BCa progression and GEM resistance by elevating S100A2 expression. Brusatol acted as a novel inhibitor of BACH1 and suppressed malignance and GEM resistance of BCa by downregulating BACH1/PSPH/S100A2 pathway.

01 Oct 2025·FREE RADICAL BIOLOGY AND MEDICINE

Targeting the NRF2 pathway with linagliptin to inhibit human hepatocellular carcinoma growth

Article

Author: Chang, Yu-Teng ; Chang, Ming-Jen ; Wu, Ming-Ju ; Chang, Chia-Che ; Shieh, Jeng-Jer

Linagliptin, a potent dipeptidyl peptidase 4 (DPP4) inhibitor, demonstrates significant potential as a therapeutic agent for hepatocellular carcinoma (HCC). This study evaluated the effects of linagliptin on HCC cell lines, focusing on mechanisms involving reactive oxygen species (ROS) production, nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation, and autophagy. Linagliptin effectively suppressed cell proliferation and induced apoptosis in HCC cell lines, particularly Hep3B cells, while sparing normal hepatic cells. It promoted ROS production and activated the NRF2 pathway and autophagy, highlighting a dual role in tumor regulation. Combination therapy with linagliptin and the NRF2 inhibitor brusatol enhanced tumor cell death, suggesting synergistic efficacy. In vivo, linagliptin reduced tumor growth in a xenograft model, with further suppression observed when combined with brusatol. These findings underscore linagliptin's therapeutic potential and its combinatorial efficacy with NRF2 inhibitors, providing a foundation for further clinical investigation in HCC treatment.

01 Sep 2025·PHYTOMEDICINE

Brusatol ameliorates irinotecan-induced delayed diarrhea via inhibition of the cGAS-STING pathway and modulation of intestinal flora

Article

Author: Chen, Baoyi ; Chen, Jiannan ; Wang, Juan ; Liu, Chunting ; Huang, Xiaoqi ; Ren, Mihong ; Xie, Jianhui ; Zhang, Yong ; Huang, Weimu ; Lai, Zixuan ; Xie, Youliang ; Lai, Zhengquan

BACKGROUND:

Irinotecan, a widely used chemotherapeutic agent, has seen its clinical application constrained by delayed diarrhea. Brucea javanica, with documented historical use in dysentery management, demonstrates anticancer synergy in its modern emulsion formulation (BJOE). Brusatol (BR), the primary bioactive compound of B. javanica, possesses anti-cancer, anti-inflammatory and anti-diarrheal properties. However, its potential effect on irinotecan-induced delayed diarrhea has yet to be explored.

PURPOSE:

The objective of this work was to experimentally explore the efficacy and action mechanism of BR in alleviating diarrhea.

METHODS:

Body weight, DAI score, colon length were measured in irinotecan-induced delayed diarrhea mouse model. The small animal imager was utilized to visualize the distribution of FITC-Dextran, and the serum fluorescence intensity was measured to assess intestinal permeability. Histopathology (HE and PAS staining), immunohistochemistry, and immunofluorescence were performed. Inflammation and barrier indices were evaluated via PCR and ELISA. Molecular docking, the STING agonist DMXAA, and 16S rRNA sequencing were employed to elucidate the possible mechanism.

RESULTS:

BR markedly ameliorated weight loss, DAI score, and colon length in mice. It also reduced intestinal permeability and pathological injury. The concentration of IL-1β, IL-6, as well as TNF-α was notably reduced by BR, while IL-10 expression was upregulated. The mRNA expression of tight junction markers ZO-1 and occludin was remarkably upregulated by BR. BR effectively restored mucin content in colonic cup cells and increase PCNA protein expression. The suppressive effect of BR on cGAS and STING was significantly reversed by DMXAA, and its effect on reducing colonic dsDNA and IFN-β protein levels was also markedly attenuated by DMXAA. Promoting STING secretion significantly attenuated the suppressive effect of BR on the cGAS-STING pathway, as evidenced by the increase of mRNA expression of cGAS, STING, CXCL10, CCL5, and IFN-β, as well as the protein expression of cGAS, STING, p-TBK1, and p-IRF3. Additionally, DMXAA attenuated BR's effect on the abundance of Proteobacteria and Bacteroidetes.

CONCLUSION:

Our study suggests that brusatol effectively mitigated irinotecan-induced delayed diarrhea, as least partially, via inhibition of aberrant activation of the cGAS-STING pathway and modulation of intestinal microbiome. Our findings may offer novel insights into the modern use of B. javanica for the treatment of diarrhea and open new avenues for the development of adjuvant anticancer drugs that alleviate irinotecan-induced intestinal adverse effects.

100 Deals associated with Brusatol

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Indication	Highest Phase	Country/Location	Organization	Date
Osteosarcoma	Preclinical	China	Zhejiang Sci-Tech University	01 Aug 2025
Osteosarcoma	Preclinical	China	Zhejiang Provincial Peoples Hospital	01 Aug 2025
Esophageal Squamous Cell Carcinoma	Preclinical	China	Anhui Medical University	04 Jun 2025
Intrahepatic Cholangiocarcinoma	Preclinical	United States	Monrovia Nursery Co., Inc.	30 Apr 2025
Intrahepatic Cholangiocarcinoma	Preclinical	United States	Beckman Research Institute of The City of Hope	30 Apr 2025
Intrahepatic Cholangiocarcinoma	Preclinical	China	Dalian Medical University	30 Apr 2025
Lymphoma	Preclinical	Austria	Medizinische Universität Graz	15 Nov 2022

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