Myocardial fibrosis—the stiffening and scarring of heart tissue—is a key component of nearly every form of heart disease, from acute ischemic injury to genetic cardiomyopathies. Over time, this mechanical stiffening impairs the heart’s ability to contract and relax, leading to progressive dysfunction and, ultimately, heart failure. Despite its widespread impact, fibrosis has remained stubbornly difficult to treat and no effective therapies are available for millions of patients today.
In
a study published this week in Nature, researchers from Stanford
Cardiovascular Institute (CVI)
report a promising new strategy for treating cardiovascular fibrosis. The approach
is two-pronged: it aims to rewire not just the biochemical signals that
initiate fibroblast activation—the process by which these scar-forming cells
are switched on—but also the mechanical cues that sustain fibrotic remodeling
over time.
"Once
fibroblasts become activated and start depositing excess protein fibers to
patch the damaged heart, it’s incredibly difficult to turn them off,” says
Sangkyun Cho, PhD, co-lead author and Instructor at the Stanford CVI. “The increased
stiffness of the fibrotic heart itself continues to activate the very cells
that cause the scarring, even after the initial pro-inflammatory signals have
subsided.”
“This
feedback loop is often overlooked in drug development and is one of the many reason
why anti-fibrotic therapies to date have not been very successful,” adds Joseph
Wu, MD, PhD, the study’s senior author and director of the Stanford CVI. “We
want to break this vicious cycle—but
until now, there’s been no reliable way to do so selectively in fibroblasts
without affecting other essential heart cell types, such as cardiomyocytes.”
To
address this challenge, the Stanford team analyzed a wide range of both public
and in-house single-cell sequencing datasets to identify a key mechanosensor
protein called SRC, which in the heart is expressed almost exclusively in stromal
cell types, most notably fibroblasts. SRC acts as a molecular switch, allowing
cells to ‘feel’ and respond to their mechanical environment. The team found
that SRC is not only enriched in cardiac fibroblasts but is also highly
activated in diseased hearts.
“We
realized that inhibiting this mechanosensor could offer a unique opportunity
for us to ‘trick’ fibroblasts—but not other heart cells— into perceiving the stiff, fibrotic
heart as soft, in vivo,” says Cho.
In
collaboration with Greenstone Biosciences, the team conducted a virtual screen of
more than 10,000 compounds to identify drugs capable of inhibiting SRC. They pinpointed
saracatinib, an orphan drug originally developed for cancer, as a promising
candidate. Treating cardiac fibroblasts with saracatinib led to marked reversal
of their activated state, closely mimicking the effects of culturing them on a
soft, healthy heart-like hydrogel.
Importantly,
when saracatinib was combined with an existing anti-fibrotic drug that blocks
TGFβ signaling—a primary trigger of fibroblast activation—the dual treatment suppressed
fibrosis and restored contractile function in multiple experimental models,
including 3D engineered heart tissues and a pre-clinical mouse model of heart
failure.
The
findings suggest that targeting SRC-driven mechanosensing, in combination with
inhibitors of upstream signals like TGFβ, could mark a new direction for
treating cardiovascular fibrosis. By disrupting both the physical and biochemical
cues that promote fibrotic remodeling—selectively in stromal cells—this dual
approach offers a promising blueprint for future ‘mechanotherapies’ aimed at
reversing, rather than merely slowing, the progression of fibrosis in the
heart.
Looking
ahead, the researchers hope to apply this strategy to other fibrotic diseases,
such as those affecting the lungs, skin, or liver.
Additional
Stanford-affiliated investigators who contributed to the study include Virginia
Winn, Y. Joseph Woo, and Helen Blau.
Full
link to the paper: https://www.nature.com/articles/s41586-025-08945-9