Hepatocellular carcinoma (HCC) is associated with a dismal prognosis. Although lipotoxicity has been shown to promote disease progression through inflammation and oxidative stress, the prognostic value of lipotoxicity-related genes (LTXGs) in HCC remains insufficiently defined. Using public transcriptomic datasets, lipotoxicity-related candidate genes were identified, and prognostic genes were screened by univariate Cox proportional hazards regression, proportional hazards (PH) assumption testing, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression analyses. A risk-score model was constructed, and a nomogram integrating the risk score and tumor stage was subsequently developed. Functional enrichment analysis, immune infiltration analysis, and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) validation were also performed. Five prognostic genes (SLC2A2, LCAT, PPARGC1A, CDKN2B, and GLP1R) were identified. Gene set enrichment analysis revealed that 35 pathways were differentially enriched between the high- and low-risk groups. Immune infiltration analysis demonstrated significantly higher infiltration of M0 macrophages in the high-risk group. RT-qPCR validation in clinical specimens confirmed that the expression levels of PPARGC1A and SLC2A2 were markedly higher in control tissues than in HCC tissues. This five-gene lipotoxicity-related signature may facilitate prognostic stratification of patients with HCC and provide a basis for further investigation of lipotoxicity-related prognostic markers.
Wenhai Ye, Yongjiang Li, Li-Na Liu et al.· Scientific Reports· 0 citations
Restoring lipid droplet (LD) content has been reported to reverse hepatic stellate cell (HSC) activation during liver fibrosis. Although the mitochondrial citrate carrier SLC25A1 is known to drive metabolic reprogramming in cancer and steatohepatitis, its specific role in regulating LDs remains unclear. This study aimed to elucidate the role of SLC25A1 in controlling LD homeostasis during HSC activation and to determine whether therapeutic inhibition of SLC25A1 could ameliorate liver fibrosis by restoring peroxisome proliferator-activated receptor-γ (PPARγ)-dependent lipid storage. Knockdown of Slc25a1 was achieved using either an adeno‑associated viral vector expressing Slc25a1 short hairpin RNA or hyaluronic acid-modified, HSC membrane-biomimetic nanovesicles containing Slc25a1 small interfering RNA (HA@JMNVs/siSlc25a1). Both approaches effectively attenuated HSC activation in three distinct mouse models, induced by carbon tetrachloride, methionine- and choline-deficient diet, and bile duct ligation, respectively. Mechanistically, SLC25A1 deficiency reduced cytosolic acetyl-coenzyme A levels in activated the human immortalized hepatic stellate cell line LX-2, resulting in reduced overall acetylation of neural precursor cell expressed, developmentally downregulated 4 (NEDD4). This reduction subsequently suppressed the NEDD4-mediated ubiquitination and degradation of PPARγ at lysine 197 (K197). The metabolic-post-translational signaling cascade increased perilipin-2 (PLIN2) transcription, inhibited lipophagy, and ultimately restored LD accumulation, thereby reversing HSC activation. Collectively, these findings establish the SLC25A1-regulated metabolic axis as a promising therapeutic target and offer a robust preclinical proof-of-concept for targeted gene therapies against liver fibrosis.
Shuqin Xue, Xiujuan Yin, Sicheng Shu et al.· Pharmacological Research· 0 citations
