SPHK1 (Sphingosine Kinase 1)

Herein, dose- and time-dependent in vitro anticancer activity studies of anti-inflammatory drugs, including celecoxib (C), indomethacin (I), and meloxicam (M), in combination with natural products (taxifolin (T), quercetin (Q), and rutin (R)) and doxorubicin (Dox), were carried out in MDA-MB-231, BT-20, MCF-7, and HT-29 human cancer cell lines. The obtained results highlight that drug C and T may be potential inhibitor candidates as SphK1 inhibitors for targeted cancer therapy. Overall, the combination of drug C with T has shown promising results, anticancer effects in breast and colon cancer cells and antiulcerative effects in rats.

FTY720, an S1P receptor antagonist, significantly inhibits ER stress-induced IEC injury. Our findings highlight the pathogenic role of host SPHK1 in gastrointestinal injury during aGVHD and suggest that targeting SPHK1 could be a therapeutic strategy for managing this condition.

Importantly, the SPHK1 inhibitor PF543 reduced abdominal hyperalgesia in mice, whereas this effect was abolished in mast cell deficient mice. Moreover, SPHK1 knockdown by siRNA abolished CRFR1-induced mast cell degranulation. These findings highlight the critical role of mast cell CRFR1 in mediating abdominal hyperalgesia and identify the MAPK/SPHK1/S1P axis as an essential pathway, suggesting that targeting mast cell CRFR1 may be a promising therapeutic strategy for managing pancreatic cancer pain.

Therefore, we propose that combining sorafenib with spermine or sphingosine could enhance its anti-HCC effects by promoting apoptosis and reducing the expression of metabolic enzymes. Moreover, Faecalibaculum may serve as a potential microbiome-based prognostic marker for HCC.

This study identifies C. sinensis-derived SPLs as key bioactive components that overcome αPD-1 resistance by targeting the SphK1-mediated Cer/S1P balance. Our findings propose a natural product-based strategy to change immunosuppressive metabolism in non-small cell lung cancer.

CHJ01 induced apoptosis by HE staining and immunohistochemistry assay. These results indicated that CHJ01 can be a potential candidate for the treatment of NSCLC.

Additionally, it functions as a novel "metabolic immune checkpoint" across multiple cancer types. SPHK1 may bridge sphingolipid metabolism with tumor immune suppression and represents a potential promising integrated target for metabolically informed immunotherapy strategies.

mTOR inhibitors, such as sirolimus, remain the cornerstone therapy, but variable treatment responses highlight the need for personalized approaches. Nevertheless, more studies are needed to better understand LAM, develop more powerful diagnostic, prognostic, and predictive biomarkers, and optimize the current treatments of LAM while developing novel therapeutic approaches.

Importantly, inhibition of the S1P/S1PR1 signaling pathway down-regulates the expression of S100A8/A9 and suppresses the growth of HPV-KI cells and xenograft derived from cervical cancer patient. These findings provide novel insights into HPV integration-induced cervical carcinogenesis and identify potential therapeutic targets for its treatment.

The results indicate that JGTCs can significantly alleviate inflammatory injury in the prostate tissue of EAP rats. Its mechanism may involve regulating intestinal microbiota dysbiosis and metabolic disorders and inhibiting the activation of the SPHK1/S1P1/PI3K/Akt signaling pathway.

Tipping the sphingolipid balance in favor of pro-apoptotic sphingolipids, through the addition of C6 ceramide or sphingosine, or through the combined pharmacologic inhibition of DEGS1 and sphingosine kinase 1, helped circumvent the cellular resistance to hypoxia-induced apoptosis in cells lacking p53. Therefore, modulating sphingolipid metabolism may be a viable approach in the treatment of solid tumors with hypoxic regions.

Shengmai San effectively attenuates irradiation-induced salivary gland hypofunction and fibrosis, mainly through inhibition of the SPHK1-S1P-S1PR1 signaling pathway.