Resistance to lenvatinib remains a major obstacle in the treatment of advanced hepatocellular carcinoma (HCC), highlighting the urgency to elucidate its underlying mechanism and identify feasible therapeutic targets. In this study, we identified a neurosecretory factor derived from hepatic cyst cells - nerve growth factor (NGF) - as a key mediator of lenvatinib resistance. Using an innovative in vivo cross-cycle strategy, we established a phenotypically stable lenvatinib-resistant HCC cell line (LenR cells). Through protein profiling of the conditioned medium and subsequent functional validation, we demonstrated that NGF secretion gradually increased as resistance was acquired. Mechanistically, we found that the SRPK1-SRSF1 axis promotes the expression of a shorter and more translationally efficient isoform (proNGF-B) by regulating the alternative splicing of its precursor transcript, thereby enhancing NGF production. The increase in NGF subsequently activates the atypical MAPK pathway (MEK5-ERK5) through its high-affinity receptor TrkA, maintaining the survival and proliferation of tumor cells under continuous tyrosine kinase inhibition pressure. Crucially, the co-targeting of TrkA with the clinically approved inhibitor larotrectinib restored lenvatinib sensitivity in patient-derived organoids and xenograft models, resulting in a significant anti-tumor synergy with no evidence of exacerbated toxicity. The clinical analysis of two independent patient cohorts further confirmed that increased NGF expression was significantly associated with poor response to lenvatinib, shorter recurrence-free periods, and poorer overall survival. Our findings reveal the crucial and previously underestimated role of tumor-derived NGF in coordinating adaptive signaling through precise post-transcriptional regulatory circuits, and propose a readily translatable biomarker-guided combination strategy to overcome lenvatinib resistance in HCC. This study was published under the title "Activation of Nerve Growth Factor signaling limits the response to lenvatinib in hepatocellular carcinoma" in Signal Transduction and Targeted Therapy.
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DOI: 10.1038/s41392-026-02649-w