Stromal or exosome derived lncRNAs regulate stemness in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains one of the most prevalent malignancies worldwide, with high recurrence rates and chemotherapy resistance posing major clinical challenges. Cancer stem cells (CSCs) are recognized as an important contributors of HCC initiation, metastasis, and recurrence. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) can maintain CSC properties through intercellular communication. Exosomes serve as essential mediators of this process by delivering long noncoding RNAs (lncRNAs) from various TME cells (including CAFs, MSCs, macrophages, and HCC cells themselves) to recipient HCC cells.

A literature search of PubMed and Web of Science Core Collection (inception to March 2026) was conducted using key terms including "HCC", "CAFs", "MSCs", "Macrophages", "Exosome", "LncRNA", and "Neoplastic Stem Cells". Studies were selected based on topic relevance and methodological rigor; those with incomplete or inaccessible data were excluded. The retrieved literature was synthesized to elucidate the mechanisms by which lncRNAs modulate downstream signaling pathways and to evaluate their translational potential as diagnostic biomarkers and therapeutic targets.

This review identifies multiple mechanisms through which stromal or exosome derived lncRNAs regulate HCC cell stemness, including YAP liquid-liquid phase separation, chromatin remodeling via recruitment of SWI/SNF, INO80, NuRD, and BRM/BRG1 complexes, Wnt/β-catenin pathway modulation through protein stabilization and competing endogenous RNA (ceRNA) networks, STAT3 pathway regulation via direct transcriptional repression and transcription factor recruitment, and BMP signaling pathway engagement. Functional classification reveals that these lncRNAs converge on core stemness pathways through complementary transcriptional, posttranscriptional, and protein-level regulatory mechanisms, while integrating signals from the TME.

Stromal or exosome derived lncRNAs constitute a critical regulatory layer in HCC stemness maintenance and hold significant promise as noninvasive diagnostic biomarkers via liquid biopsy. Antisense oligonucleotide (ASO)-based therapeutic strategies targeting the stromal cell-lncRNA-CSC axis represent a promising direction. Nevertheless, systematic characterization of stromal or exosome derived lncRNA species, elucidation of lncRNA sorting and uptake mechanisms, and clinical validation of biomarker and therapeutic applications remain important challenges for future investigation.