透明质酸（HA）是一种糖胺聚糖，是细胞外基质（ECM）的主要成分，据报道其与其受体CD44相互作用，在多种癌症干细胞（CSC）的自我更新和维持中发挥关键作用。恶性肿瘤。褪黑激素是一种具有多效抗肿瘤特性的神经内分泌激素。然而，褪黑激素是否可以调节 ECM 中 HA 的积累，从而调节头颈鳞状细胞癌 (HNSCC) 的干性仍不清楚。在这项研究中，我们发现褪黑激素抑制了 HNSCC 细胞的 CSC 相关标志物，例如 CD44，并降低了体内 CSC 的肿瘤起始频率。此外，褪黑激素通过下调透明质酸合酶3 (HAS3) 的表达来调节HNSCC 细胞的HA 合成。进一步的研究表明，Fos-like 1 (FOSL1)/HAS3 轴以不依赖于受体的方式介导褪黑素对 HNSCC 的 HA 积累和干细胞性的抑制作用。综上所述，褪黑素通过 FOSL1/HAS3 轴调节 HA 合成，抑制 HNSCC 细胞的干性，这阐明了褪黑素对 ECM 的影响，并为褪黑素在 HNSCC 治疗中的应用提供了新的视角。© 2024 John Wiley

Hyaluronic acid (HA) is a glycosaminoglycan and the main component of the extracellular matrix (ECM), which has been reported to interact with its receptor CD44 to play critical roles in the self-renewal and maintenance of cancer stem cells (CSCs) of multiple malignancies. Melatonin is a neuroendocrine hormone with pleiotropic antitumor properties. However, whether melatonin could regulate HA accumulation in the ECM to modulate the stemness of head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, we found that melatonin suppressed CSC-related markers, such as CD44, of HNSCC cells and decreased the tumor-initiating frequency of CSCs in vivo. In addition, melatonin modulated HA synthesis of HNSCC cells by downregulating the expression of hyaluronan synthase 3 (HAS3). Further study showed that the Fos-like 1 (FOSL1)/HAS3 axis mediated the inhibitory effects of melatonin on HA accumulation and stemness of HNSCC in a receptor-independent manner. Taken together, melatonin modulated HA synthesis through the FOSL1/HAS3 axis to inhibit the stemness of HNSCC cells, which elucidates the effect of melatonin on the ECM and provides a novel perspective on melatonin in HNSCC treatment.© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.