【IF 12.5】Cracking Cuproptosis Resistance in ESCC! Absin Copper Ion Assay Kit Powers Top-Tier Cell Discovery Study, Unveiling Novel Targeted-Therapy Mechanism

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November 21, 2025

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Esophageal-squamous-cell carcinoma (ESCC) remains clinically constrained by two major obstacles—chemotherapy resistance and dis-mal prognosis, with a five-year overall survival of ≈20 %. Cuproptosis, a newly validated programmed cell-death modality (2022), offers a therapeutic window, yet how metabolic reprogramming governs cuproptosis resistance is undefined. In a recent Cell Discovery article (IF = 34.9), Sun Yat-sen University Cancer Center delineates the lactate–NUDT21–FDX1–cuproptosis axis; the Absin Copper Microplate Assay Kit (cat# abs580140) provided the quantitative copper data essential for this top-tier study.

Title: NUDT21 lactylation reprograms alternative polyadenylation to promote cuproptosis resistance

Journal: Cell Discovery (IF = 34.9)

DOI: 10.1038/s41421-025-00804-1

Key reagent: Copper Microplate Assay Kit (abs580140)

I. Research Strategy: From Clinical Bottleneck to Mechanistic Closure

The authors adopted a four-step pipeline—“clinical observation → cellular validation → molecular mechanism → in-vivo therapy”—to address three cardinal questions:

1. Clinical observation: High LDHA expression correlates with low FDX1 and increased distal-poly(A) site (dPAS) usage in TCGA-ESCC cohorts, implicating a lactate–APA–cuproptosis nexus.

2. Cellular validation: L-lactate (but not D-lactate) globally lengthens 3′-UTRs in ESCC cell lines (KYSE30, TE-1); PAS-seq revealed 70.6 % and 68.1 % of APA events are 3′-UTR extensions, respectively, with FDX1 being the top hit.

3. Molecular determinant: Quantitative lactyl-proteomics identified NUDT21 (CFIm-25) as the key reader. Lactylation at K23 enhances NUDT21–CPSF6 interaction, promotes CFIm complex assembly and selectively lengthens FDX1 3′-UTR, reducing FDX1 protein abundance.

4. Therapeutic proof-of-concept: Genetic or pharmacologic inhibition of NUDT21 (LDHA inhibitor stiripentol) re-sensitizes ESCC to the copper ionophore elesclomol in vitro and in patient-derived xenografts, achieving 65 % tumor growth inhibition without overt toxicity.

II. Key Findings: Four Breakthroughs Redefining Cuproptosis Resistance in ESCC

Breakthrough 1 | L-lactate acts as a stereospecific switch for APA reprogramming

PAS-seq scatterplots demonstrate that only L-lactate significantly increases the proportion of 3′-UTR-extended transcripts (red dots), with FDX1 ranking among the top targets.

Breakthrough 2 | NUDT21-K23 lactylation is the master brake

CRISPR-directed K23R mutation abolishes lactylation, prevents FDX1 3′-UTR extension and restores FDX1 protein levels, validating K23 as the functional residue.

Breakthrough 3 | The lactate–NUDT21–FDX1 axis confers cuproptosis resistance

NUDT21 depletion re-sensitizes ESCC to elesclomol (3-fold IC₅₀ reduction), an effect fully rescued by FDX1 knockdown. Importantly, Absin Copper Microplate Assay confirmed that total copper content remained unchanged across genotypes (Suppl. Fig. S9g), rigorously excluding copper accumulation artefacts and cementing FDX1-dependent functional regulation.

Copper quantification with Absin kit

Breakthrough 4 | Clinically actionable combination: LDHA inhibitor + copper ionophore

Stiripentol (FDA-approved LDHA inhibitor) plus elesclomol shrank ESCC-PDX tumors by 65 % without body-weight loss, offering an immediately translatable therapeutic strategy.

Combination-therapy efficacy

III. Technical Highlight: Absin Copper Microplate Assay Kit—Ruling Out Copper Confounders

To attribute cuproptosis sensitization solely to the FDX1 pathway, the team had to exclude differential copper accumulation. The Absin Copper Microplate Assay Kit (abs580140) was chosen for its micro-scale compatibility with PDX samples.

Workflow: 50 mg tumor lysate → colorimetric reaction at 605 nm → quantification against a ready-to-use copper standard curve (0–50 µM).
Key result: no significant difference in total copper among control, NUDT21-KD and K23R groups (P > 0.05, Suppl. Fig. S9g), formally eliminating copper-level artefacts and reinforcing the FDX1-centric mechanism.

Feature	Benefit for study
LOD 0.1 µM	Detects minute copper changes in tumor tissue
3-step protocol, 2 h total	Rapid turnaround compatible with scarce PDX material
Ready-to-use standards & QC	Quantitative accuracy without extra optimization

Products Used in This Study

Cat. No.	Name	Size
abs580140	Copper Microplate Assay Kit	96 T

Recommended Assay Kits

Cat. No.	Product	Cited (IF)
abs580140	Copper Ion Colorimetric Kit	Adv Sci 2025 (17.5)
abs580160	L-Lactate Colorimetric Kit	Cell Commun Signal 2024 (8.4)
abs580105	Iron Ion Colorimetric Kit	Cell Biol Int 2024 (3.3)

Disclaimer: This summary is derived from the open-access article Cell Discovery (DOI: 10.1038/s41421-025-00804-1). All original figures and data are copyrighted by the journal and the authors. If any infringement is suspected, please contact us for immediate removal.

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