Cytoskeletal prestress homeostasis is a biological principle that governs living cell structure and function.

Over the last few decades, physical principles have been proposed to explain some biological processes and functions. However, biological principles remain elusive. A biological principle is a governing rule that guides the structure and functions of cells. Biological principles are built upon the laws of physics and chemistry, but they go beyond these laws and are unique to living matter. Here, we discuss what differentiates a biological principle from a physical principle and discuss candidates for biological principles. We review evidence from literature that regulation of cytoskeletal prestress (endogenous cytoskeletal pre-existing tensile stress) is essential for governing biological structures and functions of living cells. We propose that, in addition to the biological principles of Central Dogma and metabolism, cytoskeletal prestress homeostasis is a biological principle of a living cell across all domains of life. We propose that living cells regulate their stress and modulus to limit maximum strain on the cells. Homeostasis of endogenous energy-dependent, stress-supported systems that use cytoskeletal (CSK) prestress (the force of life) to stabilize structure represents a biological principle of a living cell that is not observed in inorganic systems, whereas other basic principles (e.g., self-assembly) are required for living systems but are also found in simpler nonliving systems. Leveraging biological principles of cells may have far-reaching implications in understanding the essence of cell life and designing effective interventions for therapeutics to advance medicine and enhance human health.