β-Elemene (β-ELE), derived from Curcuma wenyujin, has anticancer effect on non-small cell lung cancer (NSCLC). However, the potential target and detail mechanism were still not clear. TFEB is the master regulator of lysosome biogenesis. Ferroptosis, a promising strategy for cancer therapy could be triggered via suppression on glutathione peroxidase 4 (GPX4). Weather TFEB-mediated lysosome degradation contributes to GPX4 decline and how β-ELE modulates on this process are not clear. To observe the action of β-ELE on TFEB, and the role of TFEB-mediated GPX4 degradation in β-ELE induced ferroptosis. Surface plasmon resonance (SPR) and molecular docking were applied to observe the binding affinity of β-ELE on TFEB. Activation of TFEB and lysosome were observed by immunofluorescence, western blot, flow cytometry and qPCR. Ferroptosis induced by β-ELE was observed via lipid ROS, a labile iron pool (LIP) assay and western blot. A549^{TFEB KO} cells were established via CRISPR/Cas9. The regulation of TFEB on GPX4 and ferroptosis was observed in β-ELE treated A549^WT and A549^{TFEB KO} cells, which was further studied in orthotopic NOD/SCID mouse model. β-ELE can bind to TFEB, notably activate TFEB, lysosome and transcriptional increase on downstream gene GLA, MCOLN1, SLC26A11 involved in lysosome activity in EGFR wild-type NSCLC cells. β-ELE increased GPX4 ubiquitination and lysosomal localization, with the increase on lysosome degradation of GPX4. Furthermore, β-ELE induced ferroptosis, which could be promoted by TFEB overexpression or compromised by TFEB knockout. Genetic knockout or inactivation of TFEB compromised β-ELE induced lysosome degradation of GPX4, which was further demonstrated in orthotopic NSCLC NOD/SCID mice model. This study firstly demonstrated that TFEB promoted GPX4 lysosome degradation contributes to β-ELE induced ferroptosis in EGFR wild-type NSCLC, which gives a clue that TFEB mediated GPX4 degradation would be a novel strategy for ferroptosis induction and NSCLC therapy.

Kai-Xin-San (KXS), a Chinese herbal decoction for anti-depression, is a combination of paired-herbs, i.e. Ginseng Radix et Rhizoma (GR)-Polygalae Radix (PR) and Acori Tatarinowii Rhizoma (ATR)-Poria (PO). The make-up of the paired-herbs has been commonly revised according to syndrome differentiation and treatment variation of individual. Currently, an optimized KXS (KXS₂₀₁₂) was prepared by functional screening different combination of GR-PR and ATR-PO. The aim of this study was to verify the effect and underlying mechanism of KXS₂₀₁₂ against depression in chronic mild stress (CMS)-induced depressive rats and in primary cultures of neurons and astrocytes. In rat model, the CMS-induced depressive symptoms were markedly alleviated by the treatment with KXS₂₀₁₂. The CMS-suppressed neurotransmitter amounts were restored in the presence of KXS₂₀₁₂. And the expressions of neurotropic factors and its corresponding receptors were increased under KXS₂₀₁₂ administration. In cultured neurons, application of KXS₂₀₁₂ could promote neurogenesis by inducing the expression of synaptotagmin and dendritic spine density. Moreover, application of KXS₂₀₁₂ in cultured astrocytes, or in H₂O₂-stressed astrocytes, induced the expressions of neurotrophic factors: the increase might be associated with the modification of Erk1/2 and CREB phosphorylation. Our current results fully support the therapeutic efficacy of KXS₂₀₁₂ against depression in cell and animal models.

Yu Ping Feng San (YPFS), an ancient Chinese herbal decoction composed of Astragali Radix, Atractylodis Macrocephalae Rhizoma and Saposhnikoviae Radix, has been used in the clinic for treating immune deficiency. In cancer therapy, YPFS is being combined with chemotherapy drugs to achieve improved efficacy; however, scientific evidence to illustrate this combination effect is lacking. The present study aims to demonstrate the anti-drug resistance of YPFS in cisplatin (DDP)-resistant non-small cell lung cancer cells (A549/DDP). The application of YPFS exhibited a synergistic enhancement of DDP-induced cytotoxicity as well as of the apoptotic signalling molecules. DDP-induced expression of the multi-drug-resistance efflux transporters was markedly reduced in the presence of YPFS, resulting in a higher intracellular concentration of DDP. In addition, the application of YPFS increased DDP-induced ROS accumulation and MMP depletion, decreased p62/TRAF6 signalling in DDP-treated A549/DDP cells. The co-treatment of DDP and YPFS in tumour-bearing mice reduced the tumour size robustly (by more than 80%), which was much better than the effect of DDP alone. These results indicate that YPFS can notably improve the DDP-suppressed cancer effect, which may be a consequence of the elevation of intracellular DDP via the drug transporters as well as the down regulation of p62/TRAF6 signalling.

Immunotherapy is now a mainstay in cancer treatments. Programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitor (ICI) therapies have opened up a new venue of advanced cancer immunotherapy. However, hyperprogressive disease (HPD) induced by PD-1/PD-L1 inhibitors caused a significant decrease in the overall survival (OS) of the patients, which compromise the efficacy of PD-1/PD-L1 inhibitors. Therefore, HPD has become an urgent issue to be addressed in the clinical uses of PD-1/PD-L1 inhibitors. The mechanisms of HPD remain unclear, and possible predictive factors of HPD are not well understood. In this review, we summarized the potential mechanisms of HPD and coping strategies that can effectively reduce the occurrence and development of HPD.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a critical role in various pathological conditions, including cancer and organ injury. Post-translational modifications (PTMs) dynamically regulate ferroptosis by modulating the stability, activity, and interactions of key proteins such as GPX4, SLC7A11, and ACSL4. A single protein can undergo multiple PTMs, and the same regulatory enzyme may exert opposing effects on ferroptosis by modifying different proteins. Therefore, a comprehensive analysis of PTMs in regulatory proteins is essential for elucidating their overall impact on ferroptosis. This review systematically examines the roles of ubiquitination, ubiquitin-like modifications (e.g. UFMylation, SUMOylation), alkylation, and succination in ferroptosis regulation. We highlight how E3 ligases, deubiquitinating enzymes (DUBs), and other PTM-associated enzymes modulate ferroptosis by governing the degradation or stabilization of key targets, thereby influencing redox homeostasis and iron metabolism. Clinically, PTM-targeting agents, including E3 ligase modulators and SUMOylation inhibitors, demonstrate therapeutic potential in preclinical models, though their clinical translation remains in its early stages. This review underscores the complexity of PTM-mediated ferroptosis regulation and highlights the need to explore PTM crosstalk, refine therapeutic strategies, and develop novel PTM modulators for the treatment of malignancies and iron-related disorders.