Activin A triggers ferroptosis in tuberculosis via KAT8 and NRF2

Tuberculosis remains a major infectious disease, and understanding how immune signals influence bacterial spread and tissue damage is critical. Previous work found that Activin A, a secreted glycoprotein, is increased in people with TB and correlates with worse disease. In the study led by Kithiganahalli Narayanaswamy Balaji, researchers set out to move beyond those observations and test whether Activin A actively shapes the course of Mycobacterium tuberculosis (Mtb) infection. They focused on the Activin A–SMAD2/3 signalling pathway and its potential effects on host cell processes that might help the bacteria or worsen lung injury. Using molecular approaches, the team examined links between Activin A signalling and gene control, looking for downstream factors that change during infection. Their goal was to map a chain of events from Activin A to cellular responses that could explain how Activin A levels relate to disease severity, and to test whether interrupting this chain could change infection outcomes.

To define the molecular steps, the researchers applied molecular assays including ChIP and loss-of-function analysis to probe how Activin A acts on gene expression. Those experiments showed that Activin A and downstream SMAD2/3 signalling increase expression of lysine acetyltransferase KAT8. The team connected KAT8 activity to regulation of HO-1 levels and to Mtb-induced ferroptosis, a form of iron-dependent cell death. Mechanistically, they identified KAT8-mediated acetylation of the transcription factor NRF2 during Mtb infection; this acetylation enhanced NRF2’s availability in the nucleus and led to increased expression of HO-1. Finally, in an in vivo mouse model of TB the authors tested pharmacological inhibition of activin A receptor and KAT8, finding that both interventions restricted Mtb burden and dissemination and ameliorated TB pathology in the animals.

The study reveals a previously unrecognized role for Activin A in shaping host responses during tuberculosis by controlling KAT8 expression and the acetylation and localization of NRF2. By increasing nuclear NRF2 and HO-1, Activin A-driven KAT8 activity appears to promote ferroptosis in infected tissues, a process that could worsen damage and favor bacterial spread. Importantly, the work shows that blocking activin A receptor signalling or inhibiting KAT8 can reduce bacterial load, limit dissemination and improve disease signs in a mouse model. These findings point to Activin A, SMAD2/3, KAT8 and NRF2 as linked nodes in a host pathway that might be targeted to change disease course. While further research will be needed to move from mice to people, the study outlines a clear molecular route from a blood-borne marker to cell behaviour and disease outcome, offering a new framework for host-directed TB interventions.