Klotho, initially identified as an anti-aging gene, has been shown to play significant roles in cancer biology. Alongside α-Klotho, the β-Klotho and γ-Klotho isoforms have also been studied; these studies showed that Klotho functions as a potential tumor suppressor in many different cancers by inhibiting cancer cell proliferation, inducing apoptosis and modulating critical signaling pathways such as the Wnt/β-catenin and PI3K/Akt pathways. In cancers such as breast cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, and renal cell carcinoma, reduced Klotho expression often correlates with a poor prognosis. In addition, Klotho’s role in enhancing chemotherapy sensitivity and its epigenetic regulation further underscores its potential as a target for cancer treatments. This review details Klotho’s multifaceted contributions to cancer suppression and its potential as a therapeutic target, enhancing the understanding of its significance in cancer treatment and prognoses.

Osteosarcoma represents a rare cause of cancer in the general population, accounting for <1% of malignant neoplasms globally. Nonetheless, it represents the main cause of malignant bone neoplasm in children, adolescents and young adults under 20 years of age. It also presents another peak of incidence in people over 50 years of age and is associated with rheumatic diseases. Numerous environmental risk factors, such as bone diseases, genetics and a history of previous neoplasms, have been widely described in the literature, which allows monitoring a certain group of patients. Diagnosis requires numerous imaging tests that make it possible to stratify both the local involvement of the disease and its distant spread, which ominously determines the prognosis. Thanks to various clinical trials, the usefulness of different chemotherapy regimens, radiotherapy and surgical techniques with radical intent has now been demonstrated; these represent improvements in both prognosis and therapeutic approaches. Osteosarcoma patients should be evaluated in reference centres by multidisciplinary committees with extensive experience in proper management. Although numerous genetic and rheumatological diseases and risk factors have been described, the use of serological, genetic or other biomarkers has been limited in clinical practice compared to other neoplasms. This limits both the initial follow-up of these patients and screening in populations at risk. In addition, we cannot forget that the diagnosis is mainly based on the direct biopsy of the lesion and imaging tests, which illustrates the need to study new diagnostic alternatives. Therefore, the purpose of this study is to review the natural history of the disease and describe the main biomarkers, explaining their clinical uses, prognosis and limitations.

The IRS (insulin receptor substrate) family of scaffold proteins includes insulin receptor substrate-4 (IRS4), which is expressed only in a few cell lines, including human kidney, brain, liver, and thymus and some cell lines. Its N-terminus carries a phosphotyrosine-binding (PTB) domain and a pleckstrin homology domain (PH), which distinguishes it as a member of this family. In this paper, we collected data about the molecular mechanisms that explain the relevance of IRS4 in the development of cancer and identify IRS4 differences that distinguish it from IRS1 and IRS2. Search engines and different databases, such as PubMed, UniProt, ENSEMBL and SCANSITE 4.0, were used. We used the name of the protein that it encodes “(IRS-4 or IRS4)”, or the combination of these terms with the word “(cancer)” or “(human)”, for searches. Terms related to specific tumor pathologies (“breast”, “ovary”, “colon”, “lung”, “lymphoma”, etc.) were also used. Despite the lack of knowledge on IRS4, it has been reported that some cancers and benign tumors are characterized by high levels of IRS-4 expression. Specifically, the role of IRS-4 in different types of digestive tract neoplasms, gynecological tumors, lung cancers, melanomas, hematological tumors, and other less common types of cancers has been shown. IRS4 differs from IRS1 and IRS2 in that can activate several oncogenes that regulate the PI3K/Akt cascade, such as BRK and FER, which are characterized by tyrosine kinase-like activity without regulation via extracellular ligands. In addition, IRS4 can activate the CRKL oncogene, which is an adapter protein that regulates the MAP kinase cascade. Knowledge of the role played by IRS4 in cancers at the molecular level, specifically as a platform for oncogenes, may enable the identification and validation of new therapeutic targets.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal tumor with increasing incidence, presenting numerous clinical challenges. The histopathological examination of novel, unexplored biomarkers offers a promising avenue for research, with significant translational potential for improving patient outcomes. In this study, we evaluated the prognostic significance of ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian clock regulators (CLOCK, BMAL1, PER1, PER2), and KLOTHO in a retrospective cohort of 41 patients deceased by PDAC. Immunohistochemical techniques (IHC) and multiple statistical analyses (Kaplan–Meier curves, correlograms, and multinomial linear regression models) were performed. Our findings reveal that ferroptosis markers are directly associated with PDAC mortality, while circadian regulators and KLOTHO are inversely associated. Notably, TFRC emerged as the strongest risk marker associated with mortality (HR = 35.905), whereas CLOCK was identified as the most significant protective marker (HR = 0.01832). Correlation analyses indicate that ferroptosis markers are positively correlated with each other, as are circadian regulators, which also positively correlate with KLOTHO expression. In contrast, KLOTHO and circadian regulators exhibit inverse correlations with ferroptosis markers. Among the clinical variables examined, only the presence of chronic pathologies showed an association with the expression patterns of several proteins studied. These findings underscore the complexity of PDAC pathogenesis and highlight the need for further research into the specific molecular mechanisms driving disease progression.

Immunogenic cell death (ICD) links tumor cell demise to the activation of anti-tumor immunity, but its adoption has also generated inconsistent definitions and frequent overinterpretation of surrogate biomarkers. Here, we synthesize mechanistic and methodological evidence showing that danger-associated molecular patterns (DAMPs), cytokine release, and endoplasmic reticulum stress report immunogenic potential rather than ICD itself. We propose that ICD should be defined by its functional immunological endpoint, namely efficient antigen presentation and antigen-specific adaptive immunity, ideally culminating in protective immunological memory. To operationalize this principle, we introduce a hierarchy of experimental validation ranging from correlative hallmarks (Level 0) to innate immune integration (Level 1), antigen-specific T-cell priming (Level 2), definitive vaccination-rechallenge protection with immune-dependence testing (Level 3), and translational relevance supported by convergent human data (Level 4). We also discuss common pitfalls, equating inflammation, necrosis-associated DAMP release, or therapeutic benefit with ICD, and outline minimal immune-context controls (e.g., MHC-I, CD8⁺ T cells, Batf3-dependent dendritic cells, and innate sensing pathways) required to support robust claims. Finally, we highlight why ICD remains strongly context-dependent, shaped by dendritic-cell competence, innate licensing, purinergic metabolism, and microenvironmental constraints. Evidence-graded standards should improve reproducibility, strengthen peer review, and accelerate clinically meaningful ICD-based strategies.

Background/Objectives: Intermittent fasting (IF) has gained increasing attention as a nutritional strategy to improve metabolic health, body composition, and disease-related outcomes. However, its effects are often interpreted as broadly uniform, despite growing evidence that biological sex may modulate fasting responses. This narrative review examines sex-specific differences in the physiological, endocrine, clinical, and psychosocial effects of IF in women and men. Methods: We conducted a narrative synthesis of human and preclinical evidence addressing IF protocols, mechanisms, benefits, adverse effects, and sex-related differences. Particular attention was given to substrate metabolism, hormonal regulation, neuroendocrine sensitivity, energy availability, exercise performance, chronic disease management, aging-related outcomes, and psychological or behavioral responses. Results: The available literature suggests that women and men share several beneficial responses to IF, including improvements in body composition and cardiometabolic markers, but may differ in the magnitude, tolerability, and mechanistic basis of these effects. Women appear to show greater sensitivity of reproductive and neuroendocrine function to energetic stress, particularly under conditions of low energy availability, high exercise load, or reproductive vulnerability. In contrast, men may exhibit preserved functional outcomes despite measurable endocrine adaptations, including changes in testosterone dynamics. Across both sexes, responses vary according to fasting protocol, nutritional adequacy, baseline metabolic status, life stage, and clinical context. Conclusions: Current evidence supports a sex-informed and context-specific interpretation of IF rather than universally applicable fasting prescriptions. Direct sex-comparative studies remain scarce, and many conclusions are inferred from parallel male and female studies. Future research should integrate sex as a core biological variable in precision nutrition and fasting-based interventions.