Anaplastic thyroid cancer (ATC) is an aggressive endocrine malignancy characterized by rapid progression and limited therapeutic options. Ferritinophagy, a selective autophagic process mediated by NCOA4, regulates intracellular iron homeostasis. Here, we demonstrate that the prolyl isomerase Pin1 drives ATC progression by suppressing NCOA4-dependent ferritinophagy. Mechanistically, Pin1 recognizes phosphorylated NCOA4 through its substrate-binding WW domain. CDK2 phosphorylates NCOA4 at Ser572, creating a binding site for Pin1. This interaction promotes K29/K48-linked polyubiquitination and proteasomal degradation of NCOA4, thereby blocking ferritinophagy, lowering intracellular Fe²⁺ and lipid peroxidation, and ultimately suppressing ferroptosis. Pin1 knockdown or treatment with the pharmacological Pin1 inhibitor KPT-6566 stabilizes NCOA4, enhances ferritinophagy, and triggers ferroptosis, markedly restraining ATC growth both in vitro and in vivo. These findings identify Pin1 as a previously unrecognized suppressor of ferroptosis through NCOA4-dependent ferritinophagy and support Pin1 inhibition as a potential therapeutic strategy for ATC.

Antibody-drug conjugates (ADCs) are a new type of precise therapeutic drugs that have been widely applied in the treatment of various solid tumors and hema

Poly ADP-ribose polymerase inhibitor (PARPi) has shown promising clinical efficacy in patients with BRCA-deficient breast cancer. However, the role of metabolic reprogramming in PARPi resistance remains poorly understood. In this study, we analyzed the amino acid metabolome in samples with varying sensitivity to PARPi, revealing histidine as the most prominently dysregulated amino acid. Disruption of histidine metabolism reprogramming using liposomes containing histidine (Liposome His) effectively resensitized PARPi-resistant cells to olaparib. Mechanistically, Liposome His treatment depleted the tetrahydrofolate (THF) pool, thereby impairing nucleotide synthesis, which was particularly cytotoxic in cells with limited THF availability. Methotrexate and folate depletion further enhanced the in vitro efficacy of Liposome His. In contrast, the folate receptor antagonist mirvetuximab soravtansine exhibited potent anti-proliferative effects against PARPi-resistant cells in vivo, albeit with notable adverse effects. Combination therapy involving Liposome His and mirvetuximab soravtansine demonstrated promising inhibitory effects with manageable tolerability profiles. In addition, we preliminarily demonstrated that Liposome His regulates macrophage polarization by activating the mTOR signaling pathway, and when combined with anti-PD-L1 therapy, it jointly inhibits the pro-tumor phenotype of macrophages.