The Fibroblast Growth Factor 21 (FGF21) is considered an attractive therapeutic target for obesity and obesity-related disorders due to its beneficial effects in lipid and carbohydrate metabolism. FGF21 response is essential under stressful conditions and its metabolic effects depend on the inducer factor or stress condition. FGF21 seems to be the key signal which communicates and coordinates the metabolic response to reverse different nutritional stresses and restores the metabolic homeostasis. This review is focused on describing individually the FGF21-dependent metabolic response activated by some of the most common nutritional challenges, the signal pathways triggering this response, and the impact of this response on global homeostasis. We consider that this is essential knowledge to identify the potential role of FGF21 in the onset and progression of some of the most prevalent metabolic pathologies and to understand the potential of FGF21 as a target for these diseases. After this review, we conclude that more research is needed to understand the mechanisms underlying the role of FGF21 in macronutrient preference and food intake behavior, but also in β-klotho regulation and the activity of the fibroblast activation protein (FAP) to uncover its therapeutic potential as a way to increase the FGF21 signaling.

Epidermal growth factor receptor (EGFR) tyrosine kinases inhibitors (TKIs) are effective therapies for non-small cell lung cancer (NSCLC) patients whose tumors harbor an EGFR activating mutation. However, this treatment is not curative due to primary and secondary resistance such as T790M mutation in exon 20. Recently, activation of transducer and activator of transcription 3 (STAT3) in NSCLC appeared as an alternative resistance mechanism allowing cancer cells to elude the EGFR signaling. Overexpression of fatty acid synthase (FASN), a multifunctional enzyme essential for endogenous lipogenesis, has been related to resistance and the regulation of the EGFR/Jak2/STAT signaling pathways. Using EGFR mutated (EGFRm) NSCLC sensitive and EGFR TKIs’ resistant models (Gefitinib Resistant, GR) we studied the role of the natural polyphenolic anti-FASN compound (−)-epigallocatechin-3-gallate (EGCG), and its derivative G28 to overcome EGFR TKIs’ resistance. We show that G28’s cytotoxicity is independent of TKIs’ resistance mechanisms displaying synergistic effects in combination with gefitinib and osimertinib in the resistant T790M negative (T790M−) model and showing a reduction of activated EGFR and STAT3 in T790M positive (T790M+) models. Our results provide the bases for further investigation of G28 in combination with TKIs to overcome the EGFR TKI resistance in NSCLC.

Fibroblast growth factor 21 (FGF21) is a key hormone for metabolic homeostasis under conditions such as obesity, aging and diabetes. While extensively studied in males, its role in female physiology remains poorly defined. This study evaluated the effects of hepatic FGF21 deletion in 12-month-old female mice using a liver-specific FGF21 knockout (FKO) model. FKO females exhibited reduced body weight and improved glucose tolerance, with no changes in circulating FGF21 levels. In the liver, RT-qPCR analysis showed that the expression of genes involved in de novo lipogenesis, including Srebp1c, Fasn, and Scd1, was downregulated, whereas markers of fatty acid uptake (Cd36) and β-oxidation (Cpt1a) were upregulated without alterations in hepatic triglyceride content and lower levels of serum adiponectin. Remarkably, telomere length in both liver and adipose tissue was preserved, indicating improved cellular aging. Hepatic transcriptomic analysis revealed a global downregulation of genes linked to cytoskeletal organization, immune processes and fibrosis. Among these, Chrna4, a hepatocyte-specific nicotinic acetylcholine receptor subunit implicated in protection against metabolic-associated steatohepatitis (MASH), was significantly reduced. These findings suggest that hepatic FGF21 deficiency in aged female mice promotes metabolic health by limiting pro-inflammatory and fibrotic pathways and preserving telomere integrity, with Chrna4 emerging as a potential mediator.

The global rise in obesity and metabolic disorders has intensified interest in dietary bioactives capable of improving glycemic control and metabolic health. Inositols, particularly D-pinitol, have emerged as insulin-sensitizing cyclitols with potential metabolic relevance. Carob (Ceratonia siliqua L.), one of the richest natural sources of D-pinitol, represents a promising nutritional matrix for metabolic regulation. This narrative review critically evaluates current evidence on the role of D-pinitol in glucose homeostasis and energy balance, integrating data from chemical characterization studies, mechanistic research, preclinical models, and human clinical trials assessing purified D-pinitol and D-pinitol–rich preparations, particularly from carob-derived sources. Available evidence suggests that D-pinitol may enhance insulin signaling efficiency, primarily through PI3K/Akt-dependent pathways, modulate hepatic metabolic flexibility, and influence endocrine balance without acting as a classical hypoglycemic agent. Preclinical models consistently report improvements in insulin sensitivity, lipid handling, oxidative stress parameters, and tissue-specific metabolic adaptations. In contrast, clinical trials in healthy, prediabetic, and type 2 diabetic individuals show more heterogeneous outcomes, including attenuation of postprandial glycemia, reductions in circulating insulin and HOMA-IR, and modest improvements in lipid and inflammatory markers. Overall, carob-derived D-pinitol appears to act as a potential insulin-sensitizing metabolic modulator with context-dependent effects influenced by metabolic phenotype and food matrix composition. However, available data remains limited and heterogeneous, with most data derived from preclinical studies and relatively small clinical trials. These findings should therefore be interpreted with caution. Larger, longer-term randomized controlled trials using standardized preparations are required to establish clinical relevance and translational applicability. Notably, the contribution of other bioactive components within the carob matrix cannot be excluded.

Diet is a potential modulator of telomere length (TL), but the impact of individual dietary components, such as nuts, on TL in young, healthy individuals remains underexplored. Peanuts are rich in bioactive compounds that may influence TL. Therefore, to fill this gap of knowledge, this study aimed to investigate the effect of peanut consumption on TL in this specific population. Fifty-eight young, healthy individuals were randomized to one of three different intervention groups for 6 months each: (1) 25 g/day of skin-roasted peanuts (SRP); (2) 32 g/day of peanut butter (PB); (3) 32 g/day of a control butter (CB) (based on peanut oil). TL was measured by quantitative real-time PCR in saliva at baseline and at the end of the intervention. Our findings revealed significant between-group differences in TL changes, particularly between the SRP and CB groups over 6 months (mean difference: 0.53; 95% CI: 0.01, 1.05; p-value = 0.048). No significant difference was observed between PB and CB groups (mean difference: 0.12; 95% CI: –0.42, 0.66; p-value = 0.66). This study provides novel insights into the impact of peanut consumption on TL maintenance in young and healthy individuals. The findings highlight the potential benefits of incorporating peanuts into the diet as a means of promoting cellular health and longevity. Further research is warranted to elucidate the underlying mechanisms and validate these findings across diverse populations and longer time frames.