ZIP10 drives radioresistance and malignant progression in lung adenocarcinoma by inhibiting the Hippo pathway via a Zinc-LATS axis.

Abstract

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality globally. Although radiotherapy is a cornerstone treatment, its efficacy is severely limited by intrinsic and acquired radioresistance. Zinc transporters, particularly ZIP10, act as critical metabolic regulators in various cancers; however, their specific roles in modulating the radiation response and oncogenic signaling in LUAD remain ill-defined. Using a subcutaneous Lewis lung carcinoma (LLC) mouse model, we evaluated four hypofractionated radiotherapy regimens, identifying 8 Gy × 3 fractions as the optimal protocol for tumor regression. Transcriptomic profiling of these irradiated tumors identified ZIP10 as the most significantly downregulated gene. We employed functional assays (knockdown/overexpression) to assess the impact of ZIP10 on LUAD cell proliferation, metastasis, and radiosensitivity. Mechanistically, we investigated the zinc-dependent regulation of the Hippo pathway, focusing on the upstream kinase LATS1, using the zinc chelator TPEN and molecular analyses. Clinical analysis revealed that ZIP10 is significantly upregulated in LUAD tissues and correlates with advanced TNM stage and poor prognosis. In vitro, ZIP10 silencing markedly suppressed proliferation, migration, and invasion, while inducing G0/G1 cell cycle arrest and apoptosis. In vivo, ZIP10 depletion synergized with radiotherapy to potently inhibit tumor growth. Mechanistically, we demonstrate that ZIP10-mediated zinc influx directly inhibits the phosphorylation of LATS1, the core kinase of the Hippo pathway. This inactivation of LATS1 prevents the cytoplasmic phosphorylation of YAP/TAZ, thereby promoting their nuclear accumulation and transcriptional activity. Importantly, zinc chelation (TPEN) reversed these effects, confirming a ZIP10-Zinc-LATS1-YAP signaling axis. Our study establishes ZIP10 as a critical metabolic driver of malignant progression and radioresistance in LUAD. By inhibiting LATS1 via intracellular zinc accumulation, ZIP10 locks the Hippo pathway in an inactive state. These findings highlight ZIP10 as a promising therapeutic target for sensitizing LUAD to radiotherapy.