FDX1 (Ferredoxin 1)

This article conducts a multi-level summary from molecular mechanisms to physiological and pathological significance; deeply explores the interaction between cuproptosis and various subcellular structures, as well as their complex signal regulatory network; and systematically expounds the cutting-edge strategies for treating cuproptosis, including traditional copper chelating agents, ion carriers, and copper-based nanomedicines, with a particular focus on the latest progress in the field of natural product research. This review has systematically summarized the therapeutic potential demonstrated by numerous natural active ingredients when precisely regulating the cuproptosis pathway to provide a theoretical reference for future research in this field.

Importantly, this nanoplatform effectively targeted stubborn breast CSCs, exhibiting an IC50 as low as 13.70 ± 0.36 μg/mL─attributed to the mitochondrial targeting and subsequent inhibition of robust oxidative phosphorylation within CSCs, which rely more heavily on this pathway than on glycolysis compared to conventional cancer cells. In summary, this work presents a novel "multi-targeting" therapeutic strategy that orchestrates mitochondrial dysfunction, cuproptosis, apoptosis, and pyroptosis via a chemo-photothermal combination, offering a robust and broad-spectrum approach to eradicate both conventional resistant cancer cells and refractory CSCs.

Conversely, overexpression of PRR15 reverses this phenotype. This study reveals for the first time the regulatory mechanism of the PRR15/NF-κB/FDX1 axis in cuproptosis in RCC, providing a new strategy for the treatment of RCC patients.

KCNQ1 is a tumor suppressor of CRC that is DNA methylated. DHZCP in combination with KCNQ1 overexpression exhibits anti-CRC effects through the regulation of cuproptosis-related pathways, cuproptosis is promoted, oxidative stress is enhanced, and copper accumulates, thus supporting the clinical application prospects of DHZCP in CRC.

The Cu-Cur DTLPs developed in this study effectively induce copper-mediated death in TNBC through a dual-targeted delivery system, significantly enhancing antitumor activity with favorable safety profiles. This establishes a highly promising novel nanotherapeutic strategy for TNBC treatment.

GCSH promotes CRC progression and confers resistance to cuproptosis via the PI3K/AKT-GCSH/FDX1 axis. These findings identify GCSH as a novel regulator of cuproptosis and a potential therapeutic target in CRC.

Next, two gastric cancer cell lines (AGS, HGC27) were selected for in vitro experiments to assess the combined effects of PUN and the copper ionophore elesclomol (ES) (hereafter referred to as ES-Cu, representing the combination of ES and Cu2+)...In combination therapy strategies, PUN can work synergistically with chemotherapy drugs to suppress gastric cancer growth. Furthermore, PUN enhances its inhibitory effect on gastric cancer by working synergistically with cuproptosis through targeting FDX1.

Additionally, NaOx elevated cuproptosis in HK-2 cells, and this elevation was blocked by ZnT1 over-expression, which in turn was reversed by TTM, a cuproptosis inhibitor. This study provided evidence that Ro mitigated cuproptosis HK-2 cells induced by high oxalate through inhibiting ZnT1, thus effectively suppressing oxidative stress and crystal deposition triggered by high oxalate.

This inhibition collectively diminishes the expression and activity changes in complex IV, induces mitochondrial dysfunction, and promotes cuproptosis in ovarian cancer. This study further demonstrates that inhibiting the oxidative phosphorylation complex IV can enhance copper-induced cell death in ovarian cancer.

Knockdown or pharmacological inhibition of METTL3 sensitized HCC cells to elesclomol-Cu-induced cuproptosis and effectively suppressed HCC xenograft growth in vivo. Clinically, elevated METTL3 expression was associated with poor HCC prognosis, and the protein expression of METTL3 and FDX1 was negatively correlated in HCC tissues. In conclusion, our findings identify an METTL3-mediated m6A regulatory mechanism controlling cuproptosis sensitivity, revealing METTL3 inhibition as a promising therapeutic strategy for HCC.

This review consolidates evidence linking cuproptosis to various renal disorders, including acute kidney injury (eg, sepsis-induced, cisplatin-induced, and ischemia-reperfusion injury), diabetic nephropathy through mitochondrial dysfunction and immune dysregulation, and chronic kidney disease involving podocyte damage or context-dependent dysregulation in fibrosis and clear cell renal cell carcinoma...Future research may focus on translational applications and the physiological roles of cuproptosis in renal repair. Targeting cuproptosis offers a promising avenue for innovative diagnostics and treatments in nephrology.

This METTL3-mediated m6A modification of FDX1 accelerated BC malignant progression. Our study elucidates that the METTL3-FDX1 axis plays an instrumental role in BC progression, revealing a novel epigenetic regulatory mechanism.