Activin A

Activin A is the βA homodimer of the TGF-β superfamily - the same ligand that drives FSH secretion, embryonic mesoderm patterning, erythroid maturation, and cancer cachexia. It shares ACVR2A/B with myostatin and GDF-11, making it a critical variable in any scaffold targeting the ActRII axis. Blocking activin A alongside myostatin produces more muscle hypertrophy than myostatin blockade alone. Elevated activin A predicts poor prognosis in gastric, breast, lung, and pancreatic cancer. Every pan-ActRII trap approved for anemia or muscle disease intercepts this ligand.

INHBA (chromosome 7p14.1, 3 exons) encodes a 426-aa preproprotein. Furin cleaves after R310 to release the 116-aa (24 kDa) mature βA subunit, which homodimerizes via an interchain disulfide at C390. The mature domain adopts the canonical TGF-β cystine-knot fold - nine conserved cysteines forming intramolecular bonds plus the interchain bond. The prodomain remains noncovalently associated, holding the dimer in a partially latent state; allosteric CXXC disulfides (C35/C38) in the prodomain inhibit premature cleavage. Post-cleavage forms range from fully active A30 (both subunits cleaved, paracrine activity) to half-processed A70 and prodomain-linked A60 (juxtacrine only). Activin A binds ACVR2A/B → recruits ALK4/7 → Smad2/3 → Smad4 nuclear complex → FSH-stimulating gene transcription, erythroid maturation genes, and catabolic programs in muscle. Follistatin sequesters activin A with ~10-fold higher affinity than activin B, targeting it for lysosomal degradation.

Luspatercept (ACE-536, ActRIIA/B-Fc trap) is FDA-approved for MDS anemia and beta-thalassemia - it works in part by trapping activin A to relieve late-stage erythroid suppression. Sotatercept (similar mechanism) is approved for pulmonary arterial hypertension. No activin A–selective antibody is approved; STM 434 (anti-activin A mAb) showed stable disease in granulosa cell ovarian cancer Phase 1 without objective responses. For peptide research, the tractable recipes are: follistatin-derived peptide fragments (particularly the domain 1 binding loop) that neutralize activin A with selectivity over GDF-11; prodomain-mimetic peptides that stabilize the latent A60/A70 form to suppress local activin A activity at tumor or muscle sites; and βA mature-domain-derived inhibitory fragments that block ACVR2B engagement without cross-inhibiting GDF-8. The INHBA/INHBB heterodimer fork (activin AB) is underexplored - its differential receptor binding makes it a precision target for scaffolds needing to spare activin B–driven FSH regulation while blocking cachexia-relevant signaling.