Gut · 2026
Integrative multi-omics landscape and diagnostic-therapeutic modelling of steatohepatitic hepatocellular carcinoma.
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Zhang Laizhu, Chen Chaobo, Xu Yanchao, Zhang Yuchen, Li Huan, Wen Jingyuan, Yang Yajing, Li Yunzheng, Zhu Yican, Zong Weiwei, Zhang Yukun, Chen Tianming, Qiao Chu, Ran Bo, Gao Jialin, Han Bing, Hu Yue, Xu Chun, Chen Jun, Mai Xiaoli, Chen Jun, Liu Donglin, Xia Leizhou, Rao Jianhua, Mehal Wajahat, Li Binghua, Yu Decai
Аннотация
BACKGROUND: Steatohepatitic hepatocellular carcinoma (SH-HCC) is a distinct subtype of hepatocellular carcinoma with poorly defined molecular features and limited diagnostic and therapeutic strategies.
OBJECTIVE: This study aimed to delineate its multi-omics landscape, develop non-invasive diagnostic tools and identify actionable therapeutic targets.
DESIGN: We integrated multimodal clinical and omics datasets from an overall cohort of 156 patients, including RNA-seq (n=69), spatial transcriptomics (n=36), spatial metabolomics (n=6), lipidomics (n=125) and serum proteomics (n=152), for comprehensive molecular profiling and diagnostic model construction. FABP4 was functionally validated in Sleeping Beauty-induced HCC mouse models.
RESULTS: An SH-HCC index was established to reliably differentiate SH-HCC from conventional HCC. Drug response analysis suggested a potential reduction in responsiveness to sorafenib and immunotherapy-based regimens in SH-HCC, whereas transarterial chemoembolisation may remain an effective therapeutic option. Spatial transcriptomics revealed increased immune cell infiltration, a reinforced immune barrier and reduced tumour-immune cell communication. SH-HCC is characterised by a lipid-rich phenotype, and a diagnostic model based on 12 lipid species showed good performance in an independent cohort (area under the curve (AUC)=0.909). Serum proteomic model demonstrated good performance in the test cohort (AUC=0.828). Importantly, our preliminary findings suggest a potential therapeutic role for FABP4, as its genetic deletion suppressed tumour growth, reshaped the tumour immune microenvironment and enhanced the response to PD-1 blockade.
CONCLUSION: This study provides the first multi-omics characterisation of SH-HCC, highlighting the SH-HCC index and non-invasive diagnostic models, with FABP4 as a potential target.
OBJECTIVE: This study aimed to delineate its multi-omics landscape, develop non-invasive diagnostic tools and identify actionable therapeutic targets.
DESIGN: We integrated multimodal clinical and omics datasets from an overall cohort of 156 patients, including RNA-seq (n=69), spatial transcriptomics (n=36), spatial metabolomics (n=6), lipidomics (n=125) and serum proteomics (n=152), for comprehensive molecular profiling and diagnostic model construction. FABP4 was functionally validated in Sleeping Beauty-induced HCC mouse models.
RESULTS: An SH-HCC index was established to reliably differentiate SH-HCC from conventional HCC. Drug response analysis suggested a potential reduction in responsiveness to sorafenib and immunotherapy-based regimens in SH-HCC, whereas transarterial chemoembolisation may remain an effective therapeutic option. Spatial transcriptomics revealed increased immune cell infiltration, a reinforced immune barrier and reduced tumour-immune cell communication. SH-HCC is characterised by a lipid-rich phenotype, and a diagnostic model based on 12 lipid species showed good performance in an independent cohort (area under the curve (AUC)=0.909). Serum proteomic model demonstrated good performance in the test cohort (AUC=0.828). Importantly, our preliminary findings suggest a potential therapeutic role for FABP4, as its genetic deletion suppressed tumour growth, reshaped the tumour immune microenvironment and enhanced the response to PD-1 blockade.
CONCLUSION: This study provides the first multi-omics characterisation of SH-HCC, highlighting the SH-HCC index and non-invasive diagnostic models, with FABP4 as a potential target.