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Updated: Jan 8, 2026

Measuring Oxidative Stress Resistance of Caenorhabditis elegans in 96-well Microtiter Plates
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Measuring Oxidative Stress Resistance of Caenorhabditis elegans in 96-well Microtiter Plates

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Ribosomal RNA Synthesis is a Lethal Vulnerability During Reductive Stress In C . elegans

Jen F Rotti, Fasih Ahsan, Nicole L Stuhr

    Biorxiv : the Preprint Server for Biology
    |December 15, 2025
    PubMed

    Insights

    Toxic reductive stress, linked to metabolic diseases, can be reversed. Impaired ribosomal RNA synthesis enhances cellular resistance to reductive stress, offering a new therapeutic approach.

    Area of Science:

    • Biochemistry
    • Cell Biology
    • Genetics

    Background:

    • Reductive stress disrupts cellular redox homeostasis.
    • Accumulation of NADH and NADPH is linked to metabolic diseases like cancer and diabetes.
    • Mechanisms governing cellular responses to reductive stress require further investigation.

    Purpose of the Study:

    • To investigate the phenomenon of catastrophic reductive-death in *Caenorhabditis elegans*.
    • To explore the role of the catalytic RNA exosome subunit *crn-3* in resistance to reductive stress.
    • To identify novel mechanisms for ameliorating reductive stress-related diseases.

    Main Methods:

    • Utilized *Caenorhabditis elegans* as a model organism.
    • Employed combined biguanide treatment and *fasn-1* deficiency to induce synergistic reductive stress.
    • Investigated the effects of loss-of-function and RNAi-based knockdown of *crn-3* and other rRNA synthesis genes.

    Main Results:

    • Synergistic reductive stress correlated with aberrant nucleolar morphology.
    • Loss-of-function or knockdown of *crn-3* significantly increased resistance to toxic reductive stress.
    • Impaired ribosomal RNA biogenesis was associated with tolerance to accumulating reducing equivalents (NADPH, NADH) and prevention of GSH accumulation.

    Conclusions:

    • Identified a novel mechanism involving impaired rRNA biogenesis that confers resistance to reductive stress.
    • This mechanism offers a potential strategy for ameliorating pathologic states in reductive stress-related diseases.
    • Findings highlight the therapeutic potential of targeting rRNA synthesis for metabolic disease treatment.

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