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Cancer Cells and Metastasis / Cancer, Hypoxia, and Metabolism · Journal article
Molecular Cancer · September 9, 2026
Raises a question worth testing. It does not answer one.
This mechanistic investigation identifies a post-translational pathway—SIRT1-mediated delactylation of UQCRC2—that preserves mitochondrial fitness and enables reversible chemotherapy tolerance in colorectal cancer models. Clinical correlates link low tumor UQCRC2-K430la to poorer overall survival and high SIRT1 or low UQCRC2-K430la in circulating tumor cells to shorter progression-free survival, but these are observational associations rather than intervention outcomes.
Integrative mechanistic study combining whole-exome sequencing, multi-omics analyses, genetic and pharmacological perturbations, and retrospective clinical correlates. CRC cell lines, patient-derived xenografts, PDX-derived organoids, chemotherapy-exposed CRC tissues, and circulating tumor cells from patients with advanced CRC.. Intervention: FOLFOXIRI chemotherapy exposure; SIRT1 genetic depletion or pharmacological inhibition; PINK1 or UQCRC2 depletion. Compared with: Vehicle-treated or control cells; chemotherapy-naive cells; untreated or parental cell lines.
FOLFOXIRI-surviving CRC cells exhibited reduced proliferation without increased apoptosis and resumed growth after drug withdrawal, retaining FOLFOXIRI sensitivity upon regrowth DTP cells showed suppressed glycolytic activity, reduced lactate production, and increased reliance on oxidative phosphorylation with activation of mitophagy UQCRC2 accumulated in DTP cells and supported Parkin/SQSTM1-associated mitophagy and residual-cell survival
Depletion of PINK1 or UQCRC2 and genetic or pharmacological inhibition of SIRT1 reduced residual DTP-cell survival and delayed regrowth
The findings suggest UQCRC2-K430la as a potential biomarker of chemotherapy-associated residual disease and identify SIRT1 and UQCRC2 as candidate therapeutic vulnerabilities. However, this is a mechanistic hypothesis supported by correlative clinical data; prospective trials testing SIRT1 inhibition or UQCRC2-targeted strategies are needed before clinical implementation.
Mechanistic study in cell and animal models identifying a pathway linking lactylation to drug tolerance, with clinical associations but no prospective clinical trial or intervention outcome data.
As stated by the source record.
Quoted from the source exactly as published.
The findings suggest UQCRC2-K430la as a potential biomarker of chemotherapy-associated residual disease and identify SIRT1 and UQCRC2 as candidate therapeutic vulnerabilities. However, this is a mechanistic hypothesis supported by correlative clinical data; prospective trials testing SIRT1 inhibition or UQCRC2-targeted strategies are needed before clinical implementation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Drug-tolerant persister (DTP) cells survive anticancer therapy through reversible adaptive states and can contribute to tumor regrowth. However, how colorectal cancer (CRC) DTP cells preserve mitochondrial fitness during chemotherapy remains unclear. We investigated the metabolic and post-translational mechanisms underlying the FOLFOXIRI-induced DTP state. FOLFOXIRI-induced DTP–regrowth models were established using CRC patient-derived xenografts, PDX-derived organoids, cell lines, and cell line-derived xenografts. Whole-exome sequencing and transcriptomic, proteomic, metabolomic, and lactylomic analyses (global mass-spectrometry-based profiling of lysine lactylation sites) were integrated with genetic and pharmacological perturbations, metabolic and mitochondrial assays, protein-stability and ubiquitination analyses, and a cell-free delactylation assay, assessing the enzymatic removal of lysine lactylation. Clinical relevance was evaluated in chemotherapy-exposed CRC tissues and circulating tumor cells (CTCs). FOLFOXIRI-surviving CRC cells exhibited reduced proliferation without increased apoptosis, resumed growth after drug withdrawal, retained FOLFOXIRI sensitivity upon regrowth, and showed reversible molecular and metabolic remodeling. DTP cells displayed suppressed glycolytic activity, reduced lactate production, and increased reliance on oxidative phosphorylation, accompanied by activation of mitophagy. The mitochondrial complex III subunit UQCRC2 accumulated in DTP cells and supported Parkin (PRKN)/SQSTM1-associated mitophagy and residual-cell survival. Reduced lactate production was accompanied by decreased global lysine lactylation and reduced UQCRC2 lactylation at lysine 430 (UQCRC2-K430la). Increased UQCRC2-K430la promoted K48-linked ubiquitination and proteasome-dependent degradation of UQCRC2. SIRT1 directly delactylated UQCRC2 at K430 in an NAD + -dependent manner, thereby reducing K48-linked ubiquitination and stabilizing UQCRC2. Depletion of PINK1 or UQCRC2 and genetic or pharmacological inhibition of SIRT1 reduced residual DTP-cell survival and delayed regrowth. Among chemotherapy-responsive patients with advanced CRC, low tumor UQCRC2-K430la expression remained associated with poorer overall survival after multivariable adjustment. In paired CTC samples, increased SIRT1 or decreased UQCRC2-K430la expression after chemotherapy was associated with shorter progression-free survival. These findings identify a low-lactate/SIRT1–UQCRC2-K430la mechanism that couples glycolytic suppression to mitophagy-associated mitochondrial quality control and enables reversible chemotherapy tolerance in CRC. This pathway represents a candidate therapeutic vulnerability and supports further evaluation of UQCRC2-K430la as a biomarker of chemotherapy-associated residual disease.
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