IL-6, hepcidin, and the hidden driver of anemia in MF: Are you targeting the right pathway?
Industry Buzz
There are some theoretical ways JAK inhibition could help anemia, but [it] hasn’t really translated into consistently meaningful improvements... [This agent] came along, and it was somewhat unique. It could do the things that a normal JAK inhibitor does but then also potentially improve anemia.
—Aaron Gerds, MD, MS, hematologist-oncologist at Cleveland Clinic
Janus kinase inhibitors 1 and 2 (JAK1 and JAK2) are key therapies in myelofibrosis treatment. Despite mounting interest in this targeted therapy, JAK inhibitors often serve only to worsen patients' anemia.
“There are some theoretical ways JAK inhibition could help anemia—by reducing inflammation or shrinking the spleen—but in practice, that hasn’t really translated into consistently meaningful improvements," Aaron Gerds, MD, MS, Cleveland Clinic hematologist-oncologist and American Society of Hematology (ASH) media expert, tells MDLinx. "So overall, JAK inhibitors tend to worsen anemia."
However, Dr. Gerds says that in certain presentations, JAK inhibitors might help, noting momelotinib and pacritinib in particular.
What drives iron restriction
In response to inflammatory signaling, IL-6 binds IL-6Rα and recruits gp130 to form the active receptor complex, triggering JAK1/2 activation. This leads to STAT3 phosphorylation and nuclear translocation, where STAT3 drives hepcidin production in the liver.[]
Elevated levels of hepcidin inhibit the cellular iron transporter ferroportin. By reducing cell-surface ferroportin, hepcidin lowers intestinal iron absorption and blocks iron release from macrophages and hepatocytes. The result is lower plasma iron levels, leading to reduced erythropoiesis.[]
Hepcidin behaves like an acute phase reactant. In other words, inflammation increases hepcidin levels and impairs iron absorption, lowers serum iron and transferrin saturation, and contributes to the anemia of chronic kidney disease (CKD).
The problem with JAK inhibitors
JAK inhibitors like ruxolitinib interfere with JAK-STAT signaling and can be used to control symptoms of myelofibrosis. Their use, however, comes at a steep price, says Dr. Gerds.
“The challenge with JAK inhibitors is that they can worsen anemia. The JAK-STAT pathway is the pathway that erythropoietin uses to stimulate red blood cell production,” he says. “When you block JAK-STAT—as we do with drugs like ruxolitinib or fedratinib—you’re also blocking a pathway that’s necessary for making red blood cells. That’s why anemia is such a common side effect."
NCCN 2026 in context: How JAK inhibitor therapy is shifting
Updated 2026 guidance from NCCN on the treatment of myelofibrosis stresses risk stratification. The decision to prescribe JAK inhibitors is guided by a combination of risk category and clinical phenotype. Clinicians first stratify patients using prognostic scoring systems (eg, DIPSS or MIPSS70) into lower vs higher risk disease to determine those patients who may benefit from disease-modifying approaches, such as bone marrow transplant.
JAK inhibitor therapy is recommended for patients exhibiting higher risk disease, or for those patients with lower risk disease who are symptomatic with splenomegaly or constitutional symptoms.[]
Dr. Gerds prescribes ruxolitinib as a standard first-line therapy in patients with higher blood cell counts. He uses fedratinib as second-line treatment in patients with normal blood cell counts, and pacritinib for patients with low platelet counts. Momelotinib is preferred in patients with anemia.
“Momelotinib came along, and it was somewhat unique,” says Dr. Gerds. “It could do the things that a normal JAK inhibitor does but then also potentially improve anemia.”
Momelotinib is a kinase inhibitor used for myelofibrosis with anemia. The drug inhibits JAK1 and JAK2 to decrease constitutional symptoms and shrink spleen size, while inhibiting ACVR1 (ALK2) to lower hepcidin levels. Combined, these actions block inflammatory signaling and raise iron availability for red blood cell production.
This novel agent was approved by the FDA in 2023 as the first treatment specifically indicated for myelofibrosis patients with anemia.[] Of note, pacritinib works by the same mechanisms, with the same treatment outcomes, and is preferred in patients with thrombocytopenia.[]