The interferon-gamma response pathway is a targetable driver of FSHD muscular dystrophy progression
- 1Gene Expression Regulation Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is a leading neuromuscular disorder caused by the aberrant expression of the transcription factor double homeobox 4 (DUX4) in skeletal muscle. While DUX4 is normally restricted to early embryonic development, its reactivation in FSHD triggers chronic inflammation and progressive muscle degeneration. However, the precise molecular links between DUX4 and persistent immune activation remain poorly understood. Here, we show that DUX4 induces a viral mimicry-like pathway that is fundamentally uncoupled from canonical type I interferon (IFN) activation. Instead, DUX4 establishes a non-canonical innate immune state dominated by IFN-gamma signaling, providing a mechanistic explanation for the non-resolving inflammation characteristic of the disease. We demonstrate that while IFN-gamma treatment alone is sufficient to recapitulate key DUX4 pathogenic effects, its inhibition rescues muscle inflammation and halts disease progression in FSHD models. These findings define a skewed viral mimicry process driven by a disease-specific transcription factor and identify IFN-gamma as a primary therapeutic target for tissue-informed immunomodulation in muscular dystrophy.
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BibTeX
@misc{biferali2026interferongamma,
title = {{The interferon-gamma response pathway is a targetable driver of FSHD muscular dystrophy progression}},
author = {B. Biferali and F. Del Prete and M. Salome and J. M. Garcia Manteiga and R. Alemohammad and M. Mombellardo and M. Pannese and E. Mocciaro and F. Torri and I. Eren and E. Ferraro and D. Ballikaya and B. Ciurli and A. Votta and D. Campolungo and D. C. Turner and M. Canepari and R. Bottinelli and G. Siciliano and S. Eraslan and G. Ricci and D. Gabellini},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.758792},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.758792v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The interferon-gamma response pathway is a targetable driver of FSHD muscular dystrophy progression
AU - B. Biferali
AU - F. Del Prete
AU - M. Salome
AU - J. M. Garcia Manteiga
AU - R. Alemohammad
AU - M. Mombellardo
AU - M. Pannese
AU - E. Mocciaro
AU - F. Torri
AU - I. Eren
AU - E. Ferraro
AU - D. Ballikaya
AU - B. Ciurli
AU - A. Votta
AU - D. Campolungo
AU - D. C. Turner
AU - M. Canepari
AU - R. Bottinelli
AU - G. Siciliano
AU - S. Eraslan
AU - G. Ricci
AU - D. Gabellini
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.758792
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.758792v1
AB - Facioscapulohumeral muscular dystrophy (FSHD) is a leading neuromuscular disorder caused by the aberrant expression of the transcription factor double homeobox 4 (DUX4) in skeletal muscle. While DUX4 is normally restricted to early embryonic development, its reactivation in FSHD triggers chronic inflammation and progressive muscle degeneration. However, the precise molecular links between DUX4 and persistent immune activation remain poorly understood. Here, we show that DUX4 induces a viral mimicry-like pathway that is fundamentally uncoupled from canonical type I interferon (IFN) activation. Instead, DUX4 establishes a non-canonical innate immune state dominated by IFN-gamma signaling, providing a mechanistic explanation for the non-resolving inflammation characteristic of the disease. We demonstrate that while IFN-gamma treatment alone is sufficient to recapitulate key DUX4 pathogenic effects, its inhibition rescues muscle inflammation and halts disease progression in FSHD models. These findings define a skewed viral mimicry process driven by a disease-specific transcription factor and identify IFN-gamma as a primary therapeutic target for tissue-informed immunomodulation in muscular dystrophy.
ER -