Lactoferrin—A Regulator of Iron Homeostasis and Its Implications in Cancer Original paper

What was reviewed?

This paper presents a comprehensive narrative review of lactoferrin (LF) as a modulator of iron homeostasis and its implications in cancer, focusing on its iron-chelating, antioxidant, and immunomodulatory properties. The authors reviewed peer-reviewed literature published from 2000 to the present, prioritizing research from the last five years. The review included studies from in vitro models, human trials, and clinical interventions, particularly those exploring LF’s role in regulating iron metabolism in cancer, mitigating iron-driven oxidative stress, and influencing the gut microbiome.

Who was reviewed?

The review encompassed a diverse array of sources, including studies on cancer patients, healthy adults, pregnant women, infants, athletes, and individuals with iron-deficiency anemia (IDA). These included intervention trials using bovine or human lactoferrin, in vitro cell line studies (such as colorectal cancer cells, neuroblastoma cells, and fibroblasts), and animal models, all analyzing LF’s effectiveness in modulating oxidative stress, supporting iron homeostasis, and altering inflammatory and microbial pathways.

What were the most important findings?

Lactoferrin emerged as a potent multifunctional glycoprotein with the ability to influence systemic and cellular iron regulation—a key factor in cancer progression. By chelating free iron, LF limits its availability to cancer cells, reducing the generation of reactive oxygen species (ROS), inhibiting tumor proliferation, and even inducing ferroptosis in iron-overloaded cancer cells. LF enhances ferroportin expression, downregulates ferritin, and interacts with transferrin receptor 1, thereby modulating major iron-related proteins. LF activates antioxidant pathways, such as the Nrf2 pathway, and suppresses inflammation via inhibition of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β.

Crucially for microbiome research, the review highlights that LF supports beneficial gut microbial populations, notably Bifidobacterium and Lactobacillus, while suppressing pathogens, largely through iron sequestration and direct antimicrobial activity. Iron dysregulation in cancer patients, often driven by treatment or disease-induced inflammation, disrupts microbial balance, promoting dysbiosis. LF appears to counteract this by restoring microbial equilibrium and reducing gut inflammation.

Clinical data confirm LF’s therapeutic utility in iron-deficiency anemia and cancer-related anemia, often outperforming traditional iron salts like ferrous sulfate with fewer gastrointestinal side effects. Supplementation not only improves hematological indices but also significantly reduces IL-6 and hepcidin levels, restoring iron export pathways. Multiple human trials, especially in pregnant women and hemodialysis patients, validated LF’s superior efficacy and tolerability.

What are the implications of this review?

This review underscores lactoferrin’s potential as a novel therapeutic adjunct in oncology, particularly for patients suffering from iron metabolism disturbances and inflammation-driven tumorigenesis. Its ability to simultaneously chelate iron, suppress oxidative stress, modulate immune responses, and restore microbiome balance positions LF as a multifaceted intervention in cancer prevention and management. Importantly for clinicians, LF offers a microbiome-friendly strategy that avoids the complications of conventional iron therapies, especially in populations at risk for dysbiosis and systemic inflammation. Its compatibility with dietary and nano-formulations further enhances its translational value.