Asprosin drives obesity by triggering ferroptosis in brown fat cells

Adipose-derived asprosin, a hormone linked to obesity, appears to promote the disease by inducing ferroptosis—a form of iron-dependent cell death—in brown adipocytes, according to a new study published in Cellular & Molecular Biology Letters. The research, shared as a peer-reviewed accepted manuscript ahead of its final version of record, maps a signaling pathway through which the adipokine impairs brown adipose tissue and worsens systemic metabolism in mice.

The team behind the work set out to clarify how asprosin, an adipokine whose role in obesity had remained incompletely understood, affects whole-body metabolism and the function of brown adipose tissue, a thermogenic fat depot increasingly recognized as a key player in metabolic health. Their central hypothesis centered on ferroptosis, a regulated cell-death process, as the mechanism connecting the hormone to brown fat dysfunction.

To test this, the researchers generated mice lacking asprosin specifically in adipose tissue. They then evaluated glucose and lipid metabolism, brown adipose tissue thermogenesis, markers of ferroptosis, and downstream signaling components using biochemical assays, histological analysis, and molecular profiling. This combination allowed them to connect changes in whole-body metabolic parameters to events occurring within brown adipocytes themselves.

The results showed that adipose-specific asprosin deficiency markedly improved systemic glucose and lipid metabolism in the mice. The beneficial metabolic effect was associated with enhanced brown adipose tissue function and a significant suppression of ferroptosis in brown adipocytes. In other words, removing the hormone from adipose tissue appeared to protect brown fat cells from the iron-dependent death process while restoring their thermogenic performance.

The mechanistic core of the study lies in the Notch3 signaling pathway. According to the authors, asprosin directly binds to Notch3, a receptor whose activation normally depends on proteolytic cleavage that releases an intracellular fragment known as the Notch3 intracellular domain, or NICD. By binding the receptor, asprosin impedes this cleavage and prevents NICD from translocating to the nucleus.

That blockage has downstream consequences. The NICD fragment, when it reaches the nucleus, normally forms a transcriptional complex with RBP-Jκ, a DNA-binding protein that drives expression of target genes. Asprosin’s interference with NICD formation and nuclear entry inhibits the assembly of this NICD/RBP-Jκ complex, which in turn reduces transcription of voltage-dependent anion channel 3, or VDAC3, a gene the study identifies as a downstream target of the pathway.

Taken together, the findings support a model in which asprosin provokes brown adipose tissue dysfunction and obesity by inducing ferroptosis through inhibition of the Notch3/RBP-Jκ/VDAC3 signaling axis. The authors describe this as a novel mechanistic insight into the pathogenesis of obesity and suggest that targeting asprosin could represent a promising therapeutic strategy for metabolic disorders, though such applications remain speculative at this stage.

Several caveats frame the work. The study was conducted in mice with genetically engineered adipose-specific asprosin deficiency, and the findings have not yet been demonstrated in humans. The article is being shared early to provide faster access to peer-reviewed, accepted research; it is citable and carries a permanent DOI, but this version remains subject to further edits and will be replaced by the final version of record. The authors report no clinical trial number for the work, consistent with its preclinical design.

Within those limits, the study adds asprosin to a growing list of adipose-derived signals implicated in obesity pathogenesis, and it positions ferroptosis of brown adipocytes—regulated through a Notch3-dependent transcriptional circuit—as a process worth further investigation in metabolic disease research.

Subject of Research: The role of the adipokine asprosin in inducing ferroptosis and dysfunction of brown adipocytes via the Notch3/RBP-Jκ/VDAC3 signaling axis in obesity.

Article Title: Asprosin drives obesity by inducing ferroptosis and dysfunction of brown adipocytes mediated by Notch3/RBP-Jκ/VDAC3 axis

Article References: Chen, S., Yuan, W., Huang, Q., Xiong, X., Wang, L., Liu, W., Liu, C., Wang, Y., Wang, W., Lai, S., Zeng, G., Wan, L., & Huang, Q. (2026). Asprosin drives obesity by inducing ferroptosis and dysfunction of brown adipocytes mediated by Notch3/RBP-Jκ/VDAC3 axis. Cellular & Molecular Biology Letters. https://doi.org/10.1186/s11658-026-01034-3

Image Credits: AI Generated

DOI: 10.1186/s11658-026-01034-3

Keywords: asprosin, obesity, brown adipose tissue, ferroptosis, Notch3, RBP-Jκ, VDAC3, adipokine, metabolism, thermogenesis, preclinical study, signaling pathway