How to give cells an identity crisis

The human body experiences stress, which can impact cells at a cellular level. Cells possess protective mechanisms to detect stress, adapt, and survive. However, when stress persists, some cells may die through a process called apoptosis, traditionally viewed as both a sign of failed protective pathways and a potential cause of chronic disease.

Recent research in eLife by Thomas Rutkowski and colleagues at the University of Iowa and Shanghai Cancer Institute challenges this view, revealing new insights on cellular stress (Velarde et al., 2026).

One significant type of cellular stress originates in the endoplasmic reticulum (ER), a cell organelle responsible for protein folding and secretion. The ER is highly efficient, capable of producing substantial amounts of proteins, such as the 15 million serum albumin molecules secreted by a single liver cell every minute. However, when the ER is overwhelmed by rapid protein synthesis or affected by protein folding issues, it experiences ER stress, linked to diseases like neurodegeneration, cancer, diabetes, and cardiovascular issues (Acosta-Alvear et al., 2025).

The researchers focused on the transcription factor CHOP, which promotes cell death under ER stress. CHOP also plays a role during mild and chronic stress, even though it does not always lead to cell death during these conditions (Liu et al., 2024). To investigate CHOP's effects in mice, the researchers used liver cells engineered to lack CHOP and subjected them to tunicamycin, an ER stress inducer. Deleting CHOP altered the liver cells' stress response, reducing lipid accumulation (steatosis) - a key finding.

Further analysis using RNA-seq and ChIP-seq experiments showed CHOP suppresses genes that maintain liver cell identity and metabolism. One such gene, ONECUT1, regulates liver-specific metabolism and cell identity. Without CHOP, these cells maintained their normal metabolism program, explaining the reduced steatosis observed in mice lacking CHOP.

This suggests that chronic disease may not be a direct consequence of cell death due to stress, but rather a result of cells successfully overcoming stress but losing their identity, leading to detrimental long-term effects.

Another key discovery is that CHOP prolongs stress-induced gene expression patterns while inhibiting the emergency stress response. Normally, when the ER is overloaded with misfolded proteins, cells activate an unfolded protein response, which slows protein production, expands the ER's protein-folding capacity, and removes misfolded proteins.

This response reduces global protein production through eIF2α phosphorylation and triggers a stress-responsive gene expression program. However, CHOP helps maintain protective stress-signalling pathways even after eIF2α phosphorylation declines, leading to a shift from acute to chronic stress and disrupting fat metabolism in the liver.

This finding indicates that CHOP assists cells in adapting to ongoing stress while altering gene programmes that maintain normal identity and function.