SIRT5-mediated FDX1 desuccinylation confers cuproptosis resistance in lung adenocarcinoma.
Summary
This preclinical study identifies a SIRT5–FDX1 post-translational pathway that degrades a key cuproptosis effector and enables lung adenocarcinoma resistance. Pharmacologic SIRT5 inhibition synergized with a copper ionophore (Elesclomol-Cu) to suppress tumor growth in vivo, nominating a tractable combination strategy.
Key Findings
- Copper stress upregulates SIRT5 and reduces global protein succinylation in LUAD cells.
- SIRT5 desuccinylates FDX1 at Lys84, triggering TRIM8-mediated ubiquitination and proteasomal degradation.
- SIRT5 inhibitor MC3482 plus Elesclomol-Cu synergistically suppresses LUAD tumor growth in vivo.
Clinical Implications
Suggests biomarker-driven trials of SIRT5 inhibition plus cuproptosis inducers in lung adenocarcinoma, and assessment of FDX1 succinylation/abundance as predictors of response.
Why It Matters
Reveals a first-in-kind desuccinylation-driven resistance mechanism and provides an immediately actionable therapeutic combination with in vivo efficacy.
Limitations
- Preclinical models; absence of human interventional data.
- Safety, pharmacokinetics, and optimal dosing of SIRT5 inhibitors in humans remain undefined.
Future Directions
Translate to early-phase trials with patient stratification by SIRT5/FDX1 status and copper homeostasis; explore resistance evolution under combination therapy.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- V - Preclinical mechanistic study with in vitro and in vivo validation.
- Study Design
- OTHER