Researchers have spent years chasing ways to raise fetal hemoglobin in sickle cell and thalassemia patients. Most efforts circled around one gene: BCL11A. That changed with new work from Vijay G. Sankaran’s team at Boston Children’s Hospital and the Broad Institute. They found a separate genetic switch. It’s the BACH2–NRF2 axis. This pathway can turn on fetal hemoglobin without touching BCL11A.
The findings appeared in Nature on September 30, 2026. This is not just another tweak to the old model. The BACH2–NRF2 route works on its own, apart from BCL11A. The team used genome-wide data from more than 28,000 people. They included European, African, and Asian ancestry. This wide net helped them spot new fetal hemoglobin regulators. Harvard Medical School covered the details in their official report.
Nearly 20 years ago, human genetics first pointed to BCL11A, paving the way for gene therapies like Casgevy; this new work is presented as a continuation of that same strategy to discover novel targets.
The scientists focused on a variant called rs1010474-C. This change lowers BACH2 levels in red blood cell precursors. When BACH2 is blocked—by RNA knockdown, base editing, or a small-molecule drug—γ-globin levels jump. More red blood cells start making fetal hemoglobin. Normal blood cell growth stays on track. The results were clear. The experiments showed strong, repeatable boosts in HbF. That’s a big win for people with hemoglobin disorders.
Here’s how it works. BACH2 and NRF2 fight for control at the γ-globin promoter. Usually, BACH2 keeps NRF2 out. This limits γ-globin activation. But if BACH2 is lost or blocked, NRF2 gets in. It forms nuclear foci and ramps up γ-globin transcription. The team mapped where both proteins bind. They used base editors to make point mutations—like −98G>A, −99G>A, and −104G>A. These tweaks weaken BACH2’s hold and let NRF2 work harder. The result? A surge in fetal hemoglobin. Lab tests confirmed BACH2 and NRF2 physically interact. BACH2 dampens NRF2’s effect.
The BACH2–NRF2 pathway stands alone. It does not depend on BCL11A. According to a Dana-Farber Cancer Institute report, blocking BACH2 with drugs raises HbF in human red cell precursors. If both BACH2 and BCL11A are knocked down, the effects add up. They don’t overlap. This points to a new strategy: combine both targets to get the most HbF reactivation.
Harvard Medical School notes that researchers are already planning further studies to assess the safety and efficacy of targeting the BACH2–NRF2 axis, and are also considering combining this approach with BCL11A modulation to enhance therapeutic outcomes for patients.
Sankaran put it plainly: “The BACH2 pathway is completely independent of the BCL11A repressive pathway and is primarily involved in activation of HbF. So, combined editing at the [gamma-globin] promoters,” he told GEN, “could also be beneficial.” The authors say strong human genetic evidence—not just big effect size—best predicts clinical success. That’s why they’re confident in BACH2–NRF2 as a drug target.
Casgevy’s approval in December 2023 proved BCL11A is a real therapeutic lever. Now, BACH2–NRF2 stands as a second, druggable node. This is a big shift. Companies are already working on small molecules to hit BACH2. The new data could speed up those efforts. The field faces a new fact: fetal hemoglobin control is not a one-gene story. The next wave of sickle cell and β-thalassemia treatments may use both BCL11A and BACH2–NRF2. This is evidence-driven science. The industry should pay attention.
