FEBS Letters最新文献

To mark the 10th anniversary of the International Day of Women and Girls, FEBS Letters opened a writing contest on the topic of female role models in science. Here, we present a runner-up, an essay by Mahaiwon Shadang (All India Institute of Medical Sciences) celebrating her circle of colleagues who have built a supportive and nurturing academic environment through peer mentorship.

The fibroblast growth factor (FGF) family and the FGF receptors are ubiquitously expressed and regulate a plethora of cell signaling cascades during development, tissue and cell homeostasis, and metabolism. Dysregulated FGF signaling is associated with cancer and several genetic and metabolic disorders. As FGF signaling regulates all the key metabolic processes to maintain whole-body homeostasis, there is an increasing focus on engineering FGFs as potential treatments for dysregulated metabolism. Within cancer, reprogramming of energy metabolism is a crucial step leading to tumorigenesis, metastasis formation, and resistance to therapy. FGF signaling dysregulation in cancer enables uncontrolled proliferation and survival and promotes therapy resistance and metastasis. However, the role of FGF signaling within cancer metabolism is not well understood. A better understanding of how FGF signaling affects the rewiring of cancer metabolism as well as tumorigenesis would provide novel avenues for discovering potential drug targets and biomarkers. Here, we discuss the role of paracrine, endocrine, and intracellular FGFs within metabolism as well as the current understanding of how FGF signaling contributes to rewired cancer metabolism.

Inositol phosphates (InsPs) are intracellular signaling molecules that are essential for life. Inositol pyrophosphates, a subset of inositol phosphates, are the end products of inositol phosphate metabolism. In mammalian cells, up to 90% of inositol pyrophosphates are 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5PP-InsP₅), which is generated by inositol hexakisphosphate kinases (IP6Ks). 5PP-InsP₅ can be further phosphorylated by diphosphoinositol pentakisphosphate kinases (PPIP5Ks) to generate 1,5-bisdiphosphoinositol 2,3,4,6-tetrakisphosphate (InsP₈). Unlike freely diffusible molecules, 5PP-InsP₅ and InsP₈ act locally at the sites where they are synthesized. Thus, individual IP6K and PPIP5K enzymes perform specific functions. Preclinical and clinical studies suggest that these molecules contribute to early life development, but mediate age-related diseases beyond adulthood. In this review, we summarize the functions and mechanisms of action of every individual IP6K and PPIP5K in both physiological processes and diseases and discuss the potential applications of these inositol pyrophosphate kinases as druggable targets for disease treatment.

To mark the 10th anniversary of the International Day of Women and Girls in Science on 11th February 2025, FEBS Letters opened a writing contest on the topic of female role models in science. We invited entrants not only to reflect on the careers of prominent academics but also to share stories about the supervisors, colleagues, and other women who have inspired their own research journeys. Here, we present the winning essay, in which Rayane da Cruz Albino (Federal University of Rio de Janeiro, Brazil) discusses inspiration from a source we had not anticipated: an influential textbook, whose author, plant ecologist and field researcher Jean H. Langenheim, laid the groundwork for Albino's own budding career in ethnopharmacology.

Tropomodulin-1 (TMOD1) is a key regulator of actin filament dynamics that functions as an actin-binding protein. It specifically caps the slow-growing (pointed) ends of actin filaments, and the interaction is further stabilized by tropomyosin (TPM). By modulating actin monomer polymerization and depolymerization, TMOD1 critically controls filament length, thereby maintaining both the stability and plasticity of actin-based structures. Emerging evidence has highlighted the participation of TMOD1 in diverse cellular processes, such as cytoskeletal organization, neurite outgrowth, cell motility, and cancer progression. This review summarizes recent advances in TMOD1 research and offers a comprehensive overview of its multifaceted biological roles and implications for future studies.

Here, we present an obituary for Jaroslav Cinatl (1929–2025), a cell culture pioneer, who defended the truth and stood firm by his convictions in socialist Czechoslovakia at a high personal cost. At a time when scientific discourse faces renewed challenges, Jaroslav Cinatl's life offers a rallying counterpoint. His commitment to scientific integrity and method, pursued under threat and duress, is a beacon for the importance of scientific independence, reminding us that truth in science is not only to be discovered, but also defended.

Comprehensive understanding of phosphoinositide signaling requires both spatiotemporal visualization and precise quantitative analysis of individual lipid species. Phosphoinositides, a family of phosphorylated derivatives of phosphatidylinositol (PI), are structurally diverse lipid messengers that orchestrate a wide range of cellular functions, including membrane trafficking, cytoskeletal dynamics, and signal transduction. Due to their dynamic metabolism and compartment-specific localization, their analysis demands complementary strategies that integrate live-cell imaging with molecular quantification. In this review, we first summarize the development and application of fluorescence-based probes designed to monitor the distribution and dynamics of phosphoinositides in living cells, highlighting their specificity, targeting mechanisms, and limitations. We then provide an overview of recent advances in mass spectrometry-based methodologies that enable high-sensitivity, isomer-resolved quantification of phosphoinositides in biological specimens, including improvements in lipid extraction, derivatization, and chromatographic separation. Together, these dual approaches offer synergistic insights into the biochemical and cellular regulation of phosphoinositide signaling.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterised by nuclear TDP-43 loss. Its hallmark, cryptic exon (CE) splicing, is often masked in bulk tissue analyses by the low abundance of affected neurons. We developed an ultrasensitive RT-qPCR assay targeting STMN2 CE using one exon–CE junction-spanning primer and the other within the CE. The design expands the dynamic range sevenfold: TDP-43 knockdown boosted STMN2 CE levels 1395-fold in differentiated SH-SY5Y neurons. Spike-in tests set detection at 0.16% deficient cells. Crucially, the assay revealed a 42-fold CE increase in ALS motor cortex, previously missed by conventional primers. This streamlined tool enables precise quantification of TDP-43 dysfunction and sensitive pharmacodynamic monitoring for future ALS-FTD therapeutic studies.

In the mammalian circadian clockwork, transcriptional-translational feedback loops are mediated by the core clock proteins, CLOCK and BMAL1. Although the transcriptional activation function of the CLOCK-BMAL1 complex has been well-characterized, the mechanisms underpinning its inactivation, particularly during the repression phase, which is mediated by PER and CRY proteins, remain incompletely understood. Recent studies have shed light on the critical role of phosphorylation within the DNA-binding domains of CLOCK and BMAL1 in modulating their DNA-binding activity and enabling PER-dependent repression. In this review, we summarize landmark studies that collectively delineate a phosphorylation-mediated "displacement" model for CLOCK-BMAL1 inactivation, explore its impact on circadian period regulation, and propose a molecular mechanism that links structural modulation with transcriptional timing.

Sterol ester hydrolases (SEHs) play an important role in the quantitative regulation of sterols. Mammalian cells are known to possess SEHs both on the surface of lipid droplets and inside lysosomes. However, to date, no studies on the yeast Saccharomyces cerevisiae have identified active SEHs in the vacuole, which is the corresponding organelle to the mammalian lysosome. Here, we show that S. cerevisiae Tgl1 functions as the major SEH in the vacuole after being transported into the organelle lumen, in addition to its role in the cytoplasm. The transport of Tgl1 into the vacuole was independent of macroautophagy and ESCRT (endosomal sorting complex required for transport) complex-0 component Vps27 but dependent on ESCRT-I–III components. This study also revealed the mechanism of formation of vacuolar membrane microdomains supported by the SEHs.