The liver is the central organ for digestion and detoxification and has unique metabolic and regenerative capacities. The hepatobiliary system originates from the foregut endoderm, in which cells undergo multiple events of cell proliferation, migration, and differentiation to form the liver parenchyma and ductal system under the hierarchical regulation of transcription factors. Studies on liver development and diseases have revealed that SRY-related high-mobility group box 9 (SOX9) plays an important role in liver embryogenesis and the progression of hepatobiliary diseases. SOX9 is not only a master regulator of cell fate determination and tissue morphogenesis, but also regulates various biological features of cancer, including cancer stemness, invasion, and drug resistance, making SOX9 a potential biomarker for tumor prognosis and progression. This review systematically summarizes the latest findings of SOX9 in hepatobiliary development, homeostasis, and disease. We also highlight the value of SOX9 as a novel biomarker and potential target for the clinical treatment of major liver diseases.

The Wnt/β-catenin signaling pathway regulates many aspects of tumor biology, and many studies have focused on the role of this signaling pathway in tumor cells. However, it is now clear that tumor development and metastasis depend on the two-way interaction between cancer cells and their environment, thereby forming a tumor microenvironment (TME). In this review, we discuss how Wnt/β-catenin signaling regulates cross-interactions among different components of the TME, including immune cells, stem cells, tumor vasculature, and noncellular components of the TME in hepatocellular carcinoma. We also investigate their preclinical and clinical insights for primary liver cancer intervention, and explore the significance of using Wnt/β-catenin mutations as a biomarker to predict resistance in immunotherapy.

Early or very early detection of hepatocellular carcinoma (HCC) is an effective means to resolve the low cure rates, but there currently lacks a method that fulfills clinical requirements. One of the most prospective approaches to detecting early-stage HCC is directly testing a compendium of disease-relevant biomolecules contained within human serum through surface-enhanced Raman scattering (SERS) nanobiosensing and recognizing the biomolecular patterns. We report a novel Si-based bimetallic nanoensembles-functionalized SERS substrate (its analytical enhancement factor reaches 1.47 × 10¹²) and introduce an ultrasensitive nanobiosensing for capturing the subtle characteristic changes in SERS spectra caused by HCC, hepatitis B, or cirrhosis. Toward early diagnosis, we created an intelligent serological test with this nanobiosensing and the deep learning algorithm to gain key biomolecular phenotypes of early-stage HCC. Using clinical samples from four target populations (normal, HCC, cirrhosis, and hepatitis B), the proof-of-principle result indicates that the test yielded a predictive accuracy of 98.75% on a held-out dataset (randomly drew 4 out of 28 samples per population). On the same held-out dataset, the sensitivity and specificity of the test were both 100% for distinguishing HCC. Such a new-concept liquid biopsy could provide an opportunity for early diagnosis of HCC.