Stearoyl CoA desaturase 1 deficiency increases ferroptosis susceptibility in chicken embryonic liver cells.

Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation. It is increasingly recognized as a contributor to liver cell injury. Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme in monounsaturated fatty acid synthesis. It plays a key role in maintaining lipid homeostasis and may affect cellular susceptibility to ferroptosis. However, it remains unclear whether SCD1 restrains ferroptosis-associated injury in chicken embryonic liver (CEL) cells. Therefore, this study aimed to investigate the role of SCD1 in regulating ferroptosis susceptibility and cellular injury related to ferroptosis in CEL cells, with a focus on its effects on lipid metabolism, oxidative stress, and iron homeostasis. The results showed that SCD1 knockdown reduced intracellular lipid droplet area, triglyceride, and total cholesterol levels in CEL cells (P < 0.05). In addition, SCD1 knockdown induced mitochondrial ultrastructural changes associated with ferroptosis, including mitochondrial shrinkage, increased membrane density, and cristae disruption. It also aggravated oxidative stress, as shown by increased reactive oxygen species, oxidized glutathione, and malondialdehyde levels and decreased glutathione content (P < 0.05). SCD1 knockdown reduced cell viability, whereas oleic acid or ferrostatin-1 treatment partially reversed this decrease (P < 0.05). Moreover, SCD1 knockdown increased ACSL4 expression and decreased SLC7A11, GPX4, and Nrf2 expression at both the mRNA and protein levels (P < 0.05). SCD1 knockdown further reduced mitochondrial membrane potential and increased lipid peroxidation, intracellular Fe²⁺ levels, and total iron content (P < 0.05). In contrast, SCD1 overexpression increased lipid accumulation, reduced reactive oxygen species levels, increased glutathione content, increased SLC7A11, GPX4, and Nrf2 expression, and decreased ACSL4 protein expression (P < 0.05) without significantly affecting ACSL4 mRNA expression. These findings suggest that SCD1 regulates the susceptibility of CEL cells to ferroptosis and exerts a protective effect by improving lipid metabolism, antioxidant defenses, and mitochondrial function, indicating that SCD1 is a key regulatory factor in maintaining the homeostasis and health of chicken liver.