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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月30日

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  • Matthew Lacey,
  • Lucie Beresova,
  • Alzbeta Srovnalova,
  • Pavlo Polishchuk,
  • Michal Sala,
  • Zdenek Skrott,
  • Marian Hajduch,
  • Petr Dzubak,
  • Jiri Bartek,
  • Anna Siskova,
  • Martin Loffelmann,
  • Radim Nencka,
  • Martin Mistrik

摘要

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.