Blood Protein Lipocalin-2 Emerges as a Potential Marker of Cancer-Driven Wasting

A single molecule circulating in the blood may capture, in one measurable signal, the destructive convergence of inflammation, appetite loss and muscle depletion that defines cancer cachexia. That is the central implication of a new clinical study from Sapienza University of Rome and collaborating Italian institutions, published in Frontiers in Nutrition, which reports that patients with gastrointestinal cancer carry markedly elevated levels of lipocalin-2 (LCN2), an immune protein increasingly implicated in the regulation of appetite and energy metabolism. In a cohort of 28 treatment-naive patients, the researchers found that LCN2 levels tracked closely with pro-inflammatory cytokines and rose further in patients experiencing involuntary weight loss and reduced skeletal muscle mass, positioning the protein as a candidate biomarker for one of oncology’s most feared syndromes.

Cancer-associated anorexia and cachexia affect a striking proportion of people with advanced gastrointestinal malignancies, with estimates reaching up to 80 percent of patients with pancreatic and gastric tumors. The syndrome is far more than simple starvation: it is a multifactorial metabolic disorder in which systemic inflammation drives reduced food intake, involuntary weight loss, and the wasting of skeletal muscle and adipose tissue. The consequences are severe. Cachexia impairs quality of life, erodes tolerance to chemotherapy and surgery, and independently predicts mortality. Anorexia often appears before overt weight loss, hinting that early disruption of appetite-regulating circuits in the brain may set the stage for the metabolic collapse that follows. Yet the molecular mechanisms linking inflammation to nutritional decline remain incompletely understood, and clinicians still lack reliable circulating markers to identify patients at risk before irreversible tissue loss occurs.

Lipocalin-2, also known as neutrophil gelatinase-associated lipocalin, is an acute-phase protein long appreciated for its roles in innate immunity, iron sequestration during infection, and inflammatory responses. In recent years, however, its profile has expanded dramatically. Experimental work suggests LCN2 functions as a neuroendocrine hormone that binds the melanocortin-4 receptor in the hypothalamic paraventricular nucleus, a key node for appetite suppression, energy balance and muscle metabolism. Preclinical studies have shown that LCN2 contributes to anorexia and to the wasting of skeletal muscle and fat tissue in cancer models, including work demonstrating that the protein, secreted by tissue-infiltrating neutrophils, can induce ferroptosis in adipose and muscle tissues. Elevated circulating LCN2 has also been reported in colorectal and pancreatic cancer, where it correlates with disease progression and poor survival. What remained scarce was human data connecting LCN2 to the clinical features of cachexia in gastrointestinal cancer patients.

To address that gap, the Roman team conducted a single-center, observational, cross-sectional study enrolling 28 patients newly diagnosed with gastrointestinal cancer, the vast majority with colorectal tumors, along with 10 controls undergoing elective surgery for non-malignant conditions. All cancer patients were assessed before any surgical or oncological treatment, and individuals with conditions known to affect inflammation or nutritional status, such as active infections, renal or hepatic failure, or autoimmune disease, were excluded. Anorexia was evaluated with the validated Functional Assessment of Anorexia/Cachexia Therapy questionnaire, using a cut-off score of 30 or below, and was present in exactly half of the cancer cohort. Fasting blood samples were analyzed for LCN2 by enzyme-linked immunosorbent assay and for a panel of six cytokines, IL-6, IL-8, IL-10, IL-15, IL-18 and TNF-alpha, using multiplex Luminex technology.

Body composition added a crucial dimension. The researchers quantified skeletal muscle area on routine abdominal CT scans at the level of the third lumbar vertebra, calculating a skeletal muscle index normalized to height squared, with sex-specific internal cut-offs separating low from high muscularity. Sixteen of the 28 patients, or 57 percent, reported involuntary weight loss during the previous six months. The cohort spanned early and advanced disease, with 57 percent classified as stage I-II and 43 percent as stage III-IV, and the researchers also measured C-reactive protein, albumin, hemoglobin and renal function to contextualize the inflammatory findings.

The results were unambiguous at the group level. Serum LCN2 was significantly higher in cancer patients than in controls, and the cancer cohort showed a distinctly pro-inflammatory cytokine profile, with elevated IL-6, IL-8, IL-15 and TNF-alpha, while IL-10 and IL-18 did not differ significantly. More striking still were the correlations. Within the cancer group, LCN2 levels rose and fell in near lockstep with IL-6, yielding a Spearman correlation coefficient of 0.862, and with IL-8 at 0.789, both highly significant. LCN2 also correlated positively with IL-15 and TNF-alpha and inversely with IL-10 and IL-18, a pattern the authors interpret as evidence that the protein mirrors inflammatory dominance rather than generalized immune activation, capturing an imbalance in which catabolic signals overwhelm counter-regulatory control.

The cytokine biology behind these correlations is telling. IL-6 is a central driver of the hepatic acute-phase response, dysregulated energy expenditure and muscle protein catabolism, and has been repeatedly implicated in cachexia pathogenesis, so its tight association with LCN2 suggests the protein sits downstream of, or parallel to, canonical cachectic inflammatory pathways. The strong link with IL-8 is equally intriguing, because IL-8 orchestrates neutrophil recruitment, tumor-associated inflammation and angiogenesis, and LCN2 is abundantly released by activated neutrophils. Prior clinical work in pancreatic cancer has documented positive correlations between LCN2 and neutrophil activation markers including calprotectin, myeloperoxidase and elastase, reinforcing the idea that neutrophil-driven inflammation and systemic metabolic derangement travel together. The concurrent elevation of IL-15, which in experimental systems promotes myogenesis and can counteract TNF-alpha-induced catabolic signaling in muscle cells, alongside TNF-alpha, a classic mediator of muscle proteolysis and anorexia, may reflect a dysregulated environment in which compensatory, muscle-preserving signals coexist with dominant catabolic pathways but fail to restore balance.

When the researchers stratified patients by clinical phenotype, LCN2 tracked the severity of nutritional deterioration. Levels were higher in anorexic patients than in controls, though not significantly different between anorexic and non-anorexic patients within the cancer group, and significantly higher in patients with involuntary weight loss than in those who were weight-stable or in controls. The highest levels appeared in patients combining anorexia with weight loss, the most severe cachectic state, compared with those who had neither feature. Body composition told a similar story: LCN2 was elevated in patients with low skeletal muscle mass relative to controls, and reached its peak in the combined phenotype of low muscle mass with weight loss compared with weight-stable patients with preserved muscularity. Notably, no significant difference emerged between patients with low muscle mass plus anorexia and those with preserved muscle without anorexia, suggesting that LCN2 may be driven more by objective metabolic and nutritional decline than by appetite loss alone.

Perhaps the most clinically consequential finding came from multivariable analysis. When the researchers modeled body weight loss as the outcome and adjusted for age, sex and C-reactive protein, LCN2 remained independently associated with weight loss, with an odds ratio of 1.043 per nanogram-per-milliliter increase. This indicates that the relationship between LCN2 and wasting is not merely a proxy for the degree of systemic inflammation captured by CRP, nor an artifact of age or sex differences. Excluding patients with impaired renal function also ruled out kidney dysfunction, a known confounder of circulating LCN2, as an alternative explanation for the elevated levels.

The authors are careful about what these findings do and do not establish. The sample is small, the design is cross-sectional, and the predominance of colorectal cancer limits generalizability, while the use of internal sex-specific muscle cut-offs may complicate comparisons with other cohorts. The observational nature of the study cannot determine whether LCN2 actively drives cachexia or simply reflects inflammatory stress, and functional outcomes and survival were not assessed. Even so, the study delivers novel translational evidence that a single circulating protein integrates inflammatory burden, appetite loss, weight change and muscle depletion in gastrointestinal cancer. If longitudinal and mechanistic studies confirm that LCN2 rises early in the trajectory toward cachexia, it could become a practical tool for risk stratification, allowing clinicians to identify vulnerable patients before tissue wasting becomes irreversible, and potentially opening a new therapeutic target in a syndrome that currently has few effective options.

Subject of Research: Circulating lipocalin-2 as a biomarker of inflammation and cachexia in gastrointestinal cancer

Article Title: Circulating lipocalin-2 is associated with systemic inflammation and cachexia-related features in patients with gastrointestinal cancer

Article References: Tambaro, F., Imbimbo, G., Coletti, D., De Tullio, R., Belloni, E., Nigri, G., Costelli, P., Muscaritoli, M., & Molfino, A. (2026). Circulating lipocalin-2 is associated with systemic inflammation and cachexia-related features in patients with gastrointestinal cancer. Frontiers in Nutrition, 13, Article 1937525. https://doi.org/10.3389/fnut.2026.1937525

Image Credits: AI Generated

DOI: 10.3389/fnut.2026.1937525

Keywords: lipocalin-2, cancer cachexia, gastrointestinal cancer, anorexia, systemic inflammation, cytokines, IL-6, muscle wasting, body composition, colorectal cancer, biomarker, clinical nutrition