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  3. Autophagy revealed as a targetable vulnerability in senescent cells by cell painting phenotypic profiling: a mechanistic study of MCOPPB and related compounds

Autophagy revealed as a targetable vulnerability in senescent cells by cell painting phenotypic profiling: a mechanistic study of MCOPPB and related compounds

  • Geroscience. 2026 Apr 30. doi: 10.1007/s11357-026-02258-z.
Matthew Lacey 1 2,  Lucie Beresova 1,  Alzbeta Srovnalova 1,  Pavlo Polishchuk 1,  Michal Sala 3,  Zdenek Skrott 1 2,  Marian Hajduch 1 2,  Petr Dzubak 1 2,  Jiri Bartek 4 5,  Anna Siskova 1,  Martin Loffelmann 1,  Radim Nencka 3,  Martin Mistrik 6 7
Affiliations

Affiliations

  • 1 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic.
  • 2 Institute of Molecular and Translational Medicine, Czech Advanced Technologies and Research Institute, Palacky University, 77147, Olomouc, Czech Republic.
  • 3 Institute of Organic Chemistry and Biochemistry of the, Czech Academy of Science, CAS, Prague, Czech Republic.
  • 4 Danish Cancer Institute, Danish Cancer Society, Copenhagen, Denmark.
  • 5 Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
  • 6 Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic. [email protected].
  • 7 Institute of Molecular and Translational Medicine, Czech Advanced Technologies and Research Institute, Palacky University, 77147, Olomouc, Czech Republic. [email protected].
PMID: 42062708 DOI: 10.1007/s11357-026-02258-z
Abstract

Senescent cells accumulate with age and contribute to tissue dysfunction and chronic inflammation. Senolytic agents that selectively eliminate senescent cells hold therapeutic promise; however, few mechanistic classes have been established. Using Cell Painting-based morphological profiling, we identified a distinct cluster of senolytic compounds comprised of both known and novel Autophagy inhibitors, including AZ191, bafilomycin A1, chloroquine, daurisoline, dauricine, MCOPPB, and its derivative MS1108. These compounds selectively eliminated senescent cells by disrupting autophagic flux. Our findings reveal senescent cell dependence on Autophagy as an essential survival mechanism, define the existence of a mechanistically distinct class of senolytics acting through Autophagy inhibition, and demonstrate the predictive value of Cell Painting in aging-related drug discovery. Our results provide new insights into senescent cell vulnerability and expand the therapeutic landscape for aging-related pathologies by highlighting Autophagy as a targetable dependency.

Keywords

Autophagy; Cell Painting; Proteotoxic stress; SASP; Senescence; Senolytics.

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