bims-hypusi 2025-06-15 papers

Issue of 2025–06–15
four papers selected by
Sebastian J. Hofer, Max Delbrück Center

Cell Regen. 2025 Jun 09. 14(1): 23

eIF5A maintains intestinal epithelial homeostasis by sustaining intestinal stem cells.

Leilei Li, Yanhui Xiao, Liansheng Liu, Qianying Zhang, Yong Zhang, Dahai Zhu, Ye-Guang Chen.

Intestinal homeostasis is sustained by self-renewal of intestinal stem cells (ISCs), which continuously divide and produce proliferative transit-amplifying (TA) and then progenitor cells. Eukaryotic translation initiation factor 5A (eIF5A), a conserved translation factor, involves in a variety of cellular processes, yet its role in intestinal homeostasis remains unclear. Here, we demonstrate that eIF5A is indispensable for maintaining intestinal epithelial homeostasis. Conditional knockout of Eif5a in the adult mouse intestinal epithelium leads to stem cell loss, suppressed cell proliferation, and increased apoptosis within the crypts, concurrent with shortened gut length, reduced mouse body weight and rapid animal mortality. Consistently, Eif5a deletion in intestinal organoids also exhibits resembling cellular phenotypes. Mass spectrometry analysis reveals a significant downregulation of mitochondrial proteins, particularly those involved in mitochondrial translation, upon eIF5A depletion. Analysis of a published single-cell RNA sequencing dataset shows that mitochondrial translation-related genes, including Dars2, are highly expressed in ISC, TA and progenitor cells. Furthermore, eIF5A-deficient organoids exhibit impaired mitochondrial function, characterized by reduced ATP levels and increased reactive oxygen species (ROS). These findings highlight a critical role for eIF5A in sustaining intestinal epithelial homeostasis by regulating mitochondrial translation, providing a new insight into the molecular mechanism underlying intestinal stem cell renewal and tissue maintenance.

Keywords: Intestinal homeostasis; Intestinal stem cells; Mitochondrial translation; eIF5A

DOI: https://doi.org/10.1186/s13619-025-00243-z

Acta Pharm Sin B. 2025 Apr;15(4): 2095-2113

Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer.

Dan Feng, Jian Zhang, Huanmin Niu, Xiaoxue Zheng, Mengqi Jia, Qiqi Lu, Jing Wang, Wenxue Guo, Qi Sun, Huiqing Yuan, Hongxiang Lou.

The elevated polyamines, amine-rich molecules with diverse functions in pathophysiology processes, are implicated in contributing to tumorigenesis and progression. Whether and how they affect the efficacy of chemotherapy is incompletely understood. Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe2+ levels in vitro. Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice. Analysis of RNA-seq data indicates that heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe2+, is significantly upregulated in response to Spd and erastin cotreatment. Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1. Moreover, Spd and erastin significantly inhibit proteasome activity which results in a decrease in proteasomal degradation of NRF2, although many proteasome-related genes are induced either by Spd or Spd plus erastin. Thus, in addition to its pro-oncogenic activity, the supplement of Spd improves antitumor activity in combination with ferroptosis inducers and offers an optional approach to cancer treatment.

Keywords: EIF5A; Ferroptosis; HMOX1; NRF2; Polyamines; Prostate cancer; Proteasome; Spermidine

DOI: https://doi.org/10.1016/j.apsb.2025.02.023

Aging (Albany NY). 2025 Jun 07. 17

Spermidine supplementation and protein restriction protect from organismal and brain aging independently.

YongTian Liang, Anja Krivograd, Sebastian J Hofer, Laxmikanth Kollipara, Thomas Züllig, Albert Sickmann, Tobias Eisenberg, Stephan J Sigrist.

Brain aging and cognitive decline are significant biomedical and societal concerns. Both dietary restriction, such as limiting protein intake, and fasting, which restricts the timing of food consumption, have been proposed as strategies to delay aspects of aging. Recent studies suggest that intermittent fasting effects are mediated by the endogenous polyamine spermidine. Spermidine supplementation promotes mitochondrial integrity and functionality in aging brains by supporting hypusination of the translational initiation factor eIF5A. However, how molecular mechanisms underlying fasting mimicking interventions and protein restriction converge remain unclear, yet biomedically relevant. In this study, we combined low- and high-protein diets (2% versus 12% yeast in food) with spermidine supplementation in aging Drosophila fruit flies. Effective hypusination was essential for normal life expectancy on both 2% and 12% yeast diets. Spermidine supplementation increased longevity, protected against age-related locomotion decline on both diets and improved memory scores in older flies regardless of protein intake. Notably, spermidine did not reduce the positive effects of the 12% protein diet on fecundity. Our findings suggest that while both protein restriction and spermidine supplementation improve brain mitochondrial function, they largely operate through distinct mechanisms in modulating Drosophila brain aging. These results offer a basis for potential synergistic lifestyle interventions targeting age-related brain decline.

Keywords: aging; brain aging; mitochondria; protein restriction; spermidine

DOI: https://doi.org/10.18632/aging.206267

Discov Immunol. 2025 ;4(1): kyaf009

Spermidine suppresses DC activation via eIF5A hypusination and metabolic adaptation.

Gavin R Meehan, Utku Gunes, Larissa Camargo da Rosa, Hannah E Scales, George Finney, Ross Deehan, Sofia Sintoris, Aegli Athanasiadou, Jack Jones, Georgia Perona-Wright, James M Brewer.

Introduction: Cell metabolism plays an important role in immune effector responses and through responding to metabolic signals, immune cells can adapt and regulate their function. Arginine metabolism in dendritic cells (DC) has been shown to reduce T cell activation; however, it is unclear how this immunosuppressive state is induced.
Method: To address this issue, we examined the immunomodulatory capacity of various metabolites from arginine metabolism.
Results: Through the use of a recently described DC:T cell interaction assay and flow cytometry we demonstrated that spermidine most significantly inhibited DC activation, preventing subsequent interactions with CD4 T cells. DC function could be restored by addition of inhibitors of spermidine metabolism via the eIF5A-hypusine axis, required for expression of some mitochondrial enzymes. We also demonstrated that the spermidine induced-immunosuppressive state protected DC against activation-induced loss of mitochondrial capacity for energy generation, which was also hypusination dependent.
Conclusion: Taken together, these data demonstrate that spermidine is the key immunomodulatory component downstream of arginine metabolism and that it mediates this effect by stimulating hypusination-dependent protection of OXPHOS in DC, which in turn results in a reduced ability of DC to activate and interact with T cells. This pathway may be utilized by the immune system to regulate excessive immune responses but could also be exploited by pathogens as a method of immune evasion.

Keywords: dendritic cells; eIF5A; hypusination; immunosuppression; spermidine

DOI: https://doi.org/10.1093/discim/kyaf009