Lipid desaturation and cellular viability: mechanisms, stem cell insights, and a desaturation window model

Fatty acid (FA) desaturation is a key determinant of membrane physicochemical properties and influences multiple aspects of cellular viability and stress responses. A substantial body of evidence indicates that certain cancer cells exhibit heightened sensitivity to perturbations in FA desaturation, a feature that is also observed in cells with high differentiation potential. This sensitivity has been linked to changes in membrane composition, endoplasmic reticulum (ER) homeostasis, and signaling pathways. Insights from stem cell systems highlight the cell-type-specific nature of these processes. In particular, trophoblast stem cells (TSCs), which exhibit high monounsaturated fatty acid (MUFA) abundance, display opposite dependencies on MUFAs and express a distinct variant of stearoyl-CoA desaturase (SCD), compared with embryonic stem cells (ESCs), which are characterized by lower MUFA levels, suggesting that optimal MUFA to saturated fatty acid (SFA) ratios are required in a cell-type-specific manner. In this review, we synthesize current knowledge on the molecular and biophysical mechanisms linking FA desaturation to cellular viability, including its effects on membrane fluidity, protein function, and signaling pathways. Where stem cell-specific mechanistic data are limited, we draw on broader cellular systems to inform these mechanisms. We propose a "desaturation window" model, whereby deviations in either direction: excess saturation or insufficient saturation, disrupt membrane homeostasis and compromise cell survival. A clearer understanding of the mechanisms governing cell viability in response to FA desaturation may help explain differential sensitivities to lipid desaturation and inform therapeutic strategies in cancer and regenerative contexts.