Aims: Doxorubicin (Dox) is an effective chemotherapeutic agent, but its clinical use is limited by cardiotoxicity. Cellular senescence contributes to Dox-induced cardiac dysfunction; however, the underlying molecular mechanism mediating the effect of senescence remains poorly understood. This study aimed to identify senescence-associated factors secreted from cardiomyocytes in Dox-treated hearts and define their functional significance in Dox-induced cardiotoxicity.

Methods: Mice with cardiomyocyte-specific expression of the endoplasmic reticulum BioID secretome profiling system were used to identify Dox-induced secreted factors. Functional analyses were performed in neonatal rat ventricular myocytes (NRVMs). The effects of plasminogen activator inhibitor-1 (PAI-1) inhibition were evaluated in Dox-treated mice by assessing senescence markers, apoptotic responses, and cardiac structure and function. p21^High-tdTomato reporter mice were used to examine the fate of senescent cardiomyocytes in vivo.

Results: PAI-1 was identified as a major component of the senescence-associated secretory phenotype and was robustly upregulated in Dox-treated cardiomyocytes. In NRVMs, PAI-1 promoted senescence and maintained the senescent phenotype, in part by conferring resistance to apoptosis. Pharmacological inhibition of PAI-1 reduced senescence markers, enhanced apoptotic responses, and preserved cardiac structure and function in Dox-treated mice. Fate mapping analyses with p21^High-tdTomato mice revealed that PAI-1 inhibition decreased the number of p21^High senescent cardiomyocytes in Dox-treated hearts. Notably, PAI-1 inhibition did not attenuate Dox cytotoxicity in EO771 murine breast cancer cells.

Conclusion: PAI-1 is a key mediator of Dox-induced cardiac dysfunction. PAI-1 inhibition shifts the fate of cardiomyocytes from senescence toward apoptosis and preserves cardiac structure and function without compromising the antitumor function of Dox, highlighting PAI-1 as a potential therapeutic target for chemotherapy-associated cardiotoxicity.

The nucleolus, the largest membraneless organelle in the cell, is a biomolecular condensate that houses ribosomal DNA (rDNA), facilitates ribosomal subunit assembly, and serves as a dynamic reservoir for numerous unrelated proteins. Aging across eukaryotic species is accompanied by nucleolar expansion, raising the question of whether it is a correlate of aging or a driver of cellular aging. Recent studies suggest that nucleolar expansion may drive aging and this may result from age-associated changes in the biophysical properties of the nucleolus. Emerging evidence points to age-driven biophysical changes in the nucleolar condensate, including shifts in size, dynamics, and viscoelasticity, which may occur gradually or through transitions from a liquid-like state to denser gel-like, and in some contexts amyloid-like, assemblies. These transitions remodel two core condensate properties: compartmentalization and partitioning, with consequences for ribosome biogenesis and rDNA stability. Here, we review recent literature on age-driven changes in nucleolar condensation and discuss how these changes may influence nucleolar function and longevity.

Reproductive aging progressively impairs fertility and contributes to broader systemic decline. Stress granules (SGs), transient membraneless ribonucleoprotein assemblies formed during cellular stress, have recently emerged as important regulators of gonadal homeostasis. Their function is highly context dependent: properly resolved SGs promote cellular adaptation and survival, whereas persistent SGs disrupt proteostasis and trigger cell death pathways. In the testis, transient SGs protect germ cells under stress; however, persistent SG accumulation activates necroptosis through the ZBP1-RIPK3 axis, a pathway implicated in human non-obstructive azoospermia and testicular aging. In the ovary, defective autophagic clearance leads to pathological SG persistence in granulosa cells, while several SG-associated proteins are indispensable for normal oogenesis. Together, these findings indicate that dysregulated SG dynamics, particularly impaired clearance, represent a convergent mechanism linking cellular stress responses to reproductive decline. Despite these advances, critical gaps remain. The cell-type-specific regulation of SG assembly and disassembly within the gonad is not fully defined, and the molecular mechanisms by which persistent SGs drive tissue-level aging require clarification. Addressing these questions will refine our understanding of reproductive aging and its mechanistic connection to proteostatic imbalance.