近年来，尽管在靶向治疗和免疫治疗方面取得了巨大进展，但由于获得性化疗抵抗、复发或转移，大多数黑色素瘤患者仍需要额外的治疗。升高的自噬对黑色素瘤的发病机制至关重要，可以减轻代谢应激，保护癌细胞免受化疗药物或放射线的损害。因此，干预自噬是一种有前途的黑色素瘤治疗策略。在本研究中，我们研究了一种名为桑黄内酯H（KuH）的新型抗黑色素瘤天然化合物，发现它在体外/体内显著抑制黑色素瘤细胞生长。在机制上，KuH诱导了细胞毒性内质网（ER）应激，抑制了细胞存活并诱导了细胞凋亡。同时，KuH诱导的ER应激通过ATF4-DDIT3-TRIB3-AKT-MTOR轴介导了自噬体形成。重要的是，KuH阻碍了自噬流通，这对KuH的抗肿瘤效应起到了贡献作用。最后，我们的结果表明，KuH通过阻碍自噬对氧化应激物和受损线粒体的降解，提高了黑色素瘤细胞对顺铂的敏感性，无论是体外还是体内。我们的研究结果表明，KuH是一种有前途的黑色素瘤治疗候选天然产品。

Although great progress has been made recently in targeted and immune-based therapies, additional treatments are needed for most melanoma patients due to acquired chemoresistance, recurrence, or metastasis. Elevated autophagy is required for the pathogenesis of melanoma to attenuate metabolic stress, protecting cancer cells from chemotherapeutics or radiation. Thus, intervention with autophagy is a promising strategy for melanoma treatment. Here, we examined a novel antimelanoma natural compound named kuwanon H (KuH), which significantly inhibited melanoma cell growth in vitro/vivo. Mechanistically, KuH induced cytotoxic endoplasmic reticulum (ER) stress, which inhibited cell viability and induced apoptosis. Meanwhile, KuH-induced ER stress mediated autophagysome formation through the ATF4-DDIT3-TRIB3-AKT-MTOR axis. Importantly, KuH impaired autophagy flux, which contributed to the anticancer effects of KuH. Finally, our results showed that KuH enhanced the sensitivity of melanoma cells to cisplatin, both in vitro and in vivo, by impairing autophagy degradation of reactive oxygen species and damaged mitochondria. Our findings indicate that KuH is a promising candidate anticancer natural product for melanoma therapy.