bims-hypusi 2026-07-19 papers

Issue of 2026–07–19
two papers selected by
Sebastian J. Hofer, Max Delbrück Center

Hum Cell. 2026 Jul 18. pii: 110. [Epub ahead of print]39(8):

Targeting eIF5A2 hypusination with bikinin sensitizes hepatocellular carcinoma to lenvatinib by suppressing TFEB-mediated autophagy.

Shuqian Wang, Qingyun Zhou, Qiaomei Lin, Shufen Zhang, Ying Cai, Fangnan Wu, Fangyuan Kuang, Lianghui Wang, Shangzhi Xie, Jiahua Lan, Li Zheng, Guodong Xu, Chuxiao Shao, Wei Chen, Chaoyong Tu.

Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib, a multikinase inhibitor, necessitating the development of novel therapeutic strategies. Here, we identify bikinin as a potent eIF5A2 inhibitor through structure-based virtual screening (> 100,000 compounds) and demonstrate its synergistic effect with lenvatinib in HCC cells. Mechanistically, bikinin suppresses deoxyhypusine synthase (DHS)-mediated hypusination of eIF5A2, thereby downregulating the expression of transcription factor EB (TFEB). Furthermore, while DHS knockdown enhanced the sensitivity of HCC cells to lenvatinib, the addition of bikinin treatment provided no further significant sensitization. We also observed that the combination of bikinin and lenvatinib significantly promoted apoptosis and suppressed proliferation in HCC cells. Although TFEB overexpression conferred resistance to lenvatinib and activated autophagy, these effects were reversed by co-treatment with bikinin, which restored lenvatinib sensitivity and inhibited autophagic flux. Bikinin disrupts TFEB-driven autophagy, as evidenced by reduced LC3-II conversion, p62 accumulation, and decreased autophagosome formation. In in vivo experiments, the combination therapy with lenvatinib and bikinin achieved marked tumor regression, accompanied by suppressed Ki-67 expression and elevated TUNEL positivity. Finally, RNA-seq data identified TFEB downregulation as a critical mediator of this therapeutic sensitization. Our work unveils a novel therapeutic axis wherein targeting eIF5A2 hypusination disrupts TFEB-dependent autophagy to overcome lenvatinib resistance in HCC cells.

Keywords: Autophagy; Hepatocellular carcinoma; Hypusination; Lenvatinib; eIF5A2

DOI: https://doi.org/10.1007/s13577-026-01426-9

Cell Stress. 2026 ;10 49-52

Polyamine-mediated inhibition of ferroptosis contributes to geroprotection.

Frank Madeo, Didac Carmona-Gutierrez, Guido Kroemer.

Geroprotection aims at extending healthspan by delaying age-associated pathologies. Polyamines including spermine and spermidine are interconvertible metabolites whose longevity-promoting effects have traditionally been attributed to autophagy induction. In addition, recent evidence identifies spermine as an endogenous Fe2+ chelator that suppresses ferroptosis, thereby complementing the autophagy-inducing activity of spermidine. Indeed, spermidine inhibits EP300 acetyltransferase activity and supports hypusination-dependent activation of TFEB, both leading to autophagy. However, enhanced autophagic flux may increase susceptibility to ferroptosis through ferritinophagy and lipid remodeling. In parallel, polyamine catabolism generates H2O2 and acrolein, both of which facilitate lipid peroxidation and ferroptotic demise. The discovery that spermine directly chelates redox-active Fe2+ closes a conceptual gap by explaining how polyamine supplementation can promote longevity while avoiding excessive ferroptotic cell loss. Multiple lines of evidence including metabolomics, isotope tracing, cell-free lipid peroxidation systems, Fe2+-binding biophysics, mass spectrometry, Raman spectroscopy, nuclear magnetic resonance and disease models demonstrate that spermine limits labile iron and ferroptosis. Together, these findings support a unified model in which spermidine-driven autophagy and spermine-mediated ferroptosis inhibition cooperate to preserve tissue homeostasis and healthspan.

Keywords: Aging; autophagy; cell death; metabolism; spermidine; spermine

DOI: https://doi.org/10.15698/cst2026.07.318