Ageing is a process of continuous decline of cellular health. This decline could be attributed to loss of functions to various crucial protein players regulating the triage of cellular physiology. Systematic decline of cellular proteostasis is one major change that orchestrates alterations in functioning of other biological indicators, including cellular energetics, signal transduction, and metabolic adaptation. Among many molecular players governing physiological changes, E3 ubiquitin ligases emerge as central regulators due to their ability to confer specificity within the ubiquitin-proteasome system (UPS). They operate at crossroads of crucial pathways, like DNA damage response, oxidative stress signaling, mitochondrial homeostasis, autophagy, inflammation, and hormonal regulation. This review discusses data accumulated over decades explaining how a wide spectrum of intrinsic and extrinsic stressors, including but not limited to proteotoxic stress, metabolic imbalance, environmental and lifestyle factors modulate the expression, activity, and substrate selectivity of E3 ligases. We weighed the ubiquity of E3 ligases in various cellular processes with its regulatory importance using available literature and develop an E3 centric framework that explains how, in a context-dependent manner, the E3 ubiquitin ligases respond to changes, restore proteostasis, and stabilize internal milieu. Finally, we examine the emerging pharmacological interventions targeting E3 ubiquitin ligases and exploiting their therapeutic potential in delaying ageing-associated pathways and physiological changes. Overall, the article positions E3 ligases as context-dependent regulators of ageing and underscores several key unanswered questions essential for ageing research.
