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Updated: Jan 10, 2026
Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
Published on: October 10, 2020
GSTK1 suppresses HCC aggravation via L-carnitine metabolism by PGAM5/DRP1 complex-mediated mitochondrial quality
Yuze Shi1,2,3, Jinyao Zhang2,3,4, Bojiao Song2,3,4
1Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China.
Background:
Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality worldwide. The high recurrence rate and resistance to chemotherapy of HCC contribute to poor clinical outcomes, necessitating the development of novel therapeutic strategies. Glutathione S-transferase kappa 1 (GSTK1) is specifically localized to mitochondria and peroxisomes, participates in adiponectin secretion and insulin resistance, and inhibits the progression of non-alcoholic fatty liver disease. However, the role of GSTK1 in HCC is unknown. We aimed to determine the role of GSTK1 in HCC progression.
Methods:
N-nitrosodiethylamine (DEN)/ carbon tetrachloride and DEN/high-fat, high-fructose, high-cholesterol diet models were used in hepatocyte-specific Gstk1 knockout and control mice to establish a murine HCC model. Human HCC cell lines with GSTK1 overexpression or knockdown were used to determine GSTK1 function in tumor growth and migration in vitro. Non-target metabolomics analysis, RNA-sequence, transmission electron microscope (TEM), immunoprecipitation (IP), liquid chromatography, and high-throughput mass spectrometry (LC-MS/MS) were used to determine the mechanism by which GSTK1 participates in HCC.
Results:
GSTK1 was shown to suppress HCC in vivo and in vitro. Non-target metabolomics analysis indicated that GSTK1 participates in L-carnitine metabolism. L-carnitine supplementation inhibited proliferation and promoted apoptosis of HCC cells in vivo and in vitro. This effect was enhanced by GSTK1 overexpression. Mechanically, TEM and western blot showed that GSTK1 influences mitochondrial quality control (MQC) by promoting mitochondrial biosynthesis and mitochondrial fusion. GSTK1 was shown to inhibit mitochondrial fission and mitophagy, which was consistent with the immunofluorescence results. IP and LC-MS/LMS indicated that GSTK1 combines with PGAM5 and competes with DRP1. Additionally, GSTK1 was shown to be regulated by transcription factors (PPARα/RXRα) and the RXRα agonist, bexarotene, inhibited HCC cell proliferation.
Conclusions:
GSTK1 was shown to be a tumor suppressor via its role in MQC and L-carnitine metabolism. Bexarotene and L-carnitine supplementation may serve as potential therapeutic strategies for HCC treatment.
Insights
Glutathione S-transferase kappa 1 (GSTK1) suppresses hepatocellular carcinoma (HCC) by regulating mitochondrial quality control and L-carnitine metabolism. Bexarotene and L-carnitine show promise for HCC treatment.
Area of Science:
- Hepatology
- Oncology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) presents a significant global health challenge due to high mortality rates and treatment resistance.
- Novel therapeutic strategies are crucial for improving clinical outcomes in HCC patients.
- The specific role of Glutathione S-transferase kappa 1 (GSTK1) in HCC pathogenesis remained unexplored.
Purpose of the Study:
- To elucidate the function of GSTK1 in the progression of hepatocellular carcinoma.
- To investigate the underlying molecular mechanisms by which GSTK1 influences HCC development.
Main Methods:
- Established murine HCC models using N-nitrosodiethylamine (DEN) with chemical or dietary insults.
- Utilized human HCC cell lines with manipulated GSTK1 expression (overexpression/knockdown) for in vitro functional assays.
- Employed omics analyses (metabolomics, RNA-seq), microscopy (TEM), and biochemical assays (IP, LC-MS/MS) to determine GSTK1's mechanism of action.
Main Results:
- GSTK1 demonstrated tumor-suppressive activity against HCC both in vivo and in vitro.
- GSTK1 modulates L-carnitine metabolism, and L-carnitine supplementation inhibited HCC cell proliferation and promoted apoptosis.
- GSTK1 enhances mitochondrial quality control by promoting mitochondrial biosynthesis and fusion, while inhibiting fission and mitophagy, partly through interaction with PGAM5.
Conclusions:
- GSTK1 acts as a tumor suppressor in HCC through its influence on mitochondrial quality control and L-carnitine metabolism.
- Targeted interventions, including bexarotene and L-carnitine supplementation, represent potential therapeutic avenues for HCC treatment.
