Key result
Spermidine reverses polyamine depletion-induced cardiac ER stress by modulating PERK-ATF4 signaling.
Why the study?
Cardiac ageing and pathological stress increase vulnerability to proteostasis imbalance and ER stress, while spermidine declines with ageing. How spermidine availability and supplementation regulate the PERK-eIF2α-ATF4 ER stress axis and downstream proteostasis pathways in cardiomyocytes and the ageing heart needed to be determined.
Does spermidine supplementation regulate PERK–eIF2α–ATF4 signalling and downstream proteostasis pathways in human iPSC-derived cardiomyocytes and aged female mouse hearts?
Does spermidine supplementation regulate PERK–eIF2α–ATF4 signalling and downstream proteostasis pathways in human iPSC-derived cardiomyocytes and aged female mouse hearts?
This preclinical study identifies spermidine as a key regulator of PERK–ATF4 proteostasis and ER stress signalling in human cardiomyocytes and the ageing mouse heart, offering a potential mechanistic target for cardiac stress resilience and heart failure.
Background Cardiac ageing and pathological stress increase vulnerability to proteostasis imbalance and endoplasmic reticulum (ER) stress. PERK is a key ER stress sensor that coordinates translational control and adaptive remodelling through the PERK–eIF2α–ATF4 axis and has been implicated in cardiac stress contexts such as ischaemia–reperfusion and pressure overload. We investigated whether spermidine availability regulates PERK pathway activity in cardiomyocytes and the ageing heart. Spermidine declines with ageing and has been linked to improved autophagy, and cardiometabolic health. Purpose To determine how spermidine supplementation regulates PERK–eIF2α–ATF4 signalling and downstream proteostasis pathways in human iPSC-derived cardiomyocytes and aged female mouse hearts. Methods Human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) underwent genetic (ornithine decarboxylase 1, ODC1 silencing) and pharmacological (α-difluoromethylornithine, DFMO) depletion of endogenous spermidine synthesis, followed by spermidine treatment. PERK pathway activation and downstream proteostasis-associated signalling were assessed. In parallel, 19-month-old female C57BL/6J mice received spermidine supplementation (3 mM) for 8 weeks. Myocardial tissue was analysed for PERK-associated signalling. Results Polyamine depletion in human iPSC-CMs altered PERK pathway activity and downstream ATF4-associated stress responses. Spermidine rescue reversed these perturbations across both depletion paradigms and was accompanied by coordinated changes in proteostasis-related readouts. In aged mouse hearts, spermidine supplementation modulated PERK-associated ER stress markers. Together, these data identify spermidine as a regulator of PERK–ATF4 signalling in human cardiomyocytes and the aged heart. Conclusions These data identify PERK-driven proteostasis signalling as a mechanistic hub through which spermidine tunes stress-adaptive programs in cardiomyocytes and the ageing heart. This framework supports further mechanistic and translational work to define how polyamine-dependent ER stress modulation influences cardiac resilience and pathways relevant to heart failure.
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Kanduri et al. (2026) studied Cardiac ageing and ER stress. Spermidine supplementation vs. Polyamine depletion (ODC1 silencing or DFMO) without rescue / unsupplemented control was evaluated on PERK–eIF2α–ATF4 pathway activity and downstream proteostasis-associated signalling. Spermidine supplementation (3 mM for 8 weeks in 19-month-old female mice and in human iPSC-CMs) regulated PERK-ATF4 signalling and reversed polyamine depletion-induced ER stress perturbations.
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