Jian Lu

Background: The immunosuppressive tumor microenvironment (TME) represents a major barrier to effective hepatocellular carcinoma (HCC) therapy. While interleukin-11 (IL-11) has been implicated in cancer progression, its immunomodulatory functions and underlying mechanisms in HCC remain poorly understood. Methods: We evaluated IL-11 expression and its clinical relevance using data from public databases and clinical HCC specimens. Functional effects of IL-11 were assessed through in vitro cell culture models and in vivo orthotopic tumor experiments in mice. Regulatory T (Treg) cell differentiation and TME composition were analyzed via flow cytometry and immunohistochemistry. Molecular mechanisms were explored using Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation, and metabolic assays, focusing on the IL-11/methyl-CpG binding domain protein 3 (MBD3)/apolipoprotein H (APOH) pathway. Results: IL-11 was significantly overexpressed in HCC tissues and correlated with poor patient survival. Functionally, IL-11 enhanced the malignant phenotypes of HCC cells in vitro and in vivo , whereas its knockdown suppressed tumor migration and growth. Importantly, IL-11 increased the proportion of Treg cells in the HCC microenvironment by driving their differentiation, thereby fostering an immunosuppressive TME. Mechanistically, IL-11 upregulated MBD3, which transcriptionally repressed APOH. This downregulation activated the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ (PPARγ)-mediated fatty acid oxidation (FAO) pathway, and pharmacological inhibition of FAO effectively reversed IL-11-induced Treg differentiation and tumor growth. Conclusion: We have identified a novel IL-11/MBD3/APOH/FAO regulatory axis that promotes HCC progression by enhancing Treg cell differentiation and establishing an immunosuppressive microenvironment. These results nominate IL-11 as a promising therapeutic target for HCC immunotherapy and shed new light on the metabolic basis of immune evasion in liver cancer.

Hepatocellular carcinoma (HCC) cells sustain viability and radioresistance by actively countering oxidative stress. Understanding the mechanisms regulating reactive oxygen species (ROS) homeostasis is therefore crucial for developing novel therapies. Using integrated genome-wide CRISPR-Cas9 screening coupled with transcriptomic and metabolomic profiling, we identified DDB1 and CUL4-associated factor 4 (DCAF4) as an essential regulator of oxidative stress resistance in HCC. Mechanistically, DCAF4 functions as a CRL4 E3 ligase adapter that promotes KEAP1 ubiquitination and degradation. Notably, under oxidative stress, cytoplasmic stress granules (SGs) form a localized platform that facilitates the DCAF4–KEAP1 interaction, accelerating KEAP1 degradation and leading to NRF2 activation and upregulation of antioxidant genes. We further identified that the transcription factor XBP1 enhances DCAF4 expression. Targeting this axis, we performed computational screening to identify a small-molecule inhibitor that disrupts the DCAF4–KEAP1 interaction. This compound effectively enhanced brachytherapy (BT) sensitivity and inhibited tumor growth in preclinical HCC models.

In recent years, the technology of targeted protein degradation (TPD) has developed rapidly. Proteolysis targeting chimeras (PROTACs) have achieved remarka

Metastasis is a primary cause of cancer-related mortality, and the liver is the most common site of tumor metastasis. The molecular heterogeneity and complex tumor microenvironment of liver metastases remain major barriers contributing to clinical treatment failure. The dearth of accurate metastatic liver tumor models leads to a paucity of understanding regarding the mechanisms of liver metastasis and limits the exploration of novel therapeutic approaches. Patient-derived organoids provide a three-dimensional, tissue-engineered, cell-based in vitro model that reproduces the complex structure and function of the corresponding in vivo tissue. The advent of this personalized paradigm, tailored to the specific needs of individual patients, has enabled the translation of foundational research into clinical applications. This review provides a comprehensive summary of various methods for culturing liver metastatic cancer organoids, highlighting the novel findings and clinical applicability of organoids in liver metastasis research. It also discusses current research achievements and recent advances in liver metastatic cancer organoids.

Interventional brachytherapy, such as iodine-125(¹²⁵I), has improved the survival of obstructive late-stage esophageal cancer patients. However, most patients experience radioresistance after ¹²⁵I brachytherapy. It is key to decipher the underlying mechanism of ¹²⁵I radioresistance. In this study, we identified an endoplasmic reticulum-associated protein, P4HA2, which is upregulated and mediates resistance to ¹²⁵I treatment. Mechanistically, P4HA2 enhances mitochondrial autophagy (mitophagy) via the PINK1/parkin pathway by binding to ATAD3A. Clinically, high expression of P4HA2 correlates with shorter overall survival and predicts poor prognosis with ¹²⁵I brachytherapy. Moreover, the expression of P4HA2 is epigenetically increased by IGF2BP2 in an m⁶A-dependent manner. Notably, targeting P4HA2 with siRNA-based biocompatible nanomedicines significantly sensitizes ESCC to ¹²⁵I brachytherapy. Collectively, our results show the molecular mechanism of mitophagy-mediated ¹²⁵I radioresistance, which provides a potential therapeutic target and combinatorial strategy.