ALDH1L2 drives HCC progression through TAM polarization.

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Dysregulated one-carbon metabolism is linked to mitochondrial dysfunction and cancer.
• Aldehyde dehydrogenase 1 family member L2 (ALDH1L2) is implicated in tumor progression, but its role in hepatocellular carcinoma (HCC) is unclear.

Purpose of the Study:

• To investigate the role and molecular mechanisms of ALDH1L2 in HCC progression.
• To explore ALDH1L2 as a potential therapeutic target in HCC.

Main Methods:

• Evaluated ALDH1L2 expression in HCC tissues and cell lines using immunohistochemistry, western blotting, and immunofluorescence.
• Conducted in vitro and in vivo assays to determine ALDH1L2's functional role and regulatory pathways in HCC.

Main Results:

• ALDH1L2 upregulation correlates with poor HCC prognosis (HR=1.923, p=0.04).
• ALDH1L2 promotes HCC cell proliferation and metastasis via NRF2/IL-6/STAT3 signaling activation.
• ALDH1L2 enhances mitochondrial respiration, ATP production, and ROS-induced damage protection through NRF2 stabilization, forming a positive feedback loop.
• ALDH1L2 interacts with tumor-associated macrophages, promoting HCC progression.
• ALDH1L2 knockdown sensitizes HCC cells to sorafenib.

Conclusions:

• ALDH1L2 is a key driver of HCC progression, interacting with tumor-associated macrophages via Jak2/STAT3 signaling.
• ALDH1L2 serves as a prognostic marker and potential therapeutic target for HCC.
• Targeting ALDH1L2 may improve the efficacy of sorafenib in HCC treatment.