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Researchers at the University of Pennsylvania have developed a gene-editing platform designed specifically for filamentous fungi, enabling scientists to access potentially useful molecules that fungi normally do not produce under laboratory conditions. The tool, called fPE7max, achieved editing efficiencies approaching 90% across several fungal species. The research, led by Penn professor Xue “Sherry” Gao with first author Chunxiao Sun, was published in the journal Nature Biotechnology.
Filamentous fungi, including members of the Aspergillus and Penicillium genera, are established sources of medically important compounds. Penicillin and several cholesterol-lowering statins originated from fungi — as Gao put it, “from the serendipitous discovery of penicillin to cholesterol-lowering statins, we owe many recent breakthroughs in longevity to fungal chemistry.” However, researchers believe that much of the fungal kingdom’s chemical diversity remains inaccessible because many biosynthetic pathways become inactive when fungi are cultivated under controlled laboratory conditions.
In natural environments, competition, nutrient limitations, and other pressures can activate gene clusters responsible for producing defensive or biologically active compounds. Without these signals, the clusters remain silent, preventing researchers from identifying the molecules encoded within the fungal genome.
The research team, led by University of Pennsylvania professor Xue “Sherry” Gao, developed fPE7max to overcome the limitations of conventional CRISPR-Cas9 editing. CRISPR-Cas9 cuts both strands of DNA, which can cause unintended mutations and make precise genetic changes difficult in filamentous fungi. Prime editing instead rewrites targeted DNA sequences without creating a complete double-strand break.
Adapting prime editing to fungal cells required the researchers to address two major obstacles. Long guide RNA sequences, which direct the editing system to its target, can degrade before an edit is completed. The team incorporated a stabilizing protein called fLa to protect these RNA instructions — an early version of this protein, borrowed from humans, did not work inside fungal cells, and switching to a fungus’s own version of the protein was what made the system function.
Fungal repair systems can also detect and reverse newly introduced genetic changes. To prevent this response, the researchers added a specialized protein that temporarily suppresses the fungus’s natural repair mechanism, allowing the edited genetic code to become permanent.
To test the platform, the team targeted laeA, a master regulatory gene that controls multiple fungal biosynthetic pathways. By removing molecular sequences that repress laeA translation, researchers activated previously silent gene clusters across several fungal species.
The edited fungi produced 18 structurally complex molecules. Eight had chemical structures that had not previously been reported — several belonging to a chemical family called pyranonigrins. Three of the newly identified molecules demonstrated early anti-cancer activity in laboratory testing. One showed selective toxicity against human breast, hepatic, and leukemia cancer cells.
These findings do not establish the molecules as cancer treatments. The experiments were conducted using cell-based laboratory models, and the compounds have not yet been evaluated in animals or humans. Researchers describe the study as a proof of concept, with the molecules serving as leads for further investigation rather than drug candidates ready for clinical development — first author Chunxiao Sun noted that “these molecules can serve as lead compounds for disease treatment, providing a vital new pipeline for drug discovery.”
The team plans to apply fPE7max across a broader range of fungal species. By systematically activating silent biosynthetic pathways, researchers hope to create a more efficient approach for identifying fungal molecules with possible pharmaceutical value. As Gao described it, “it’s a compelling proof-of-concept demonstrating that the next generation of life-saving therapeutics might already exist in nature.”
References
Penn Today (2026). Unearthing new cancer treatments from fungi.
Phys.org (2026). How a new fungal genome-editing tool could open fresh paths to cancer treatments.
According to mycostories
