A newly recognized class of single-domain polyphenol oxidases (PPOs) in ascomycetes, termed short PPOs, can sequentially hydroxylate and oxidize guaiacyl- and, in some cases, syringyl-type compounds, leading to oxidative demethoxylation of the latter [1]. Their activity on lignin-derived compounds is novel among PPOs and the catalyzed reaction differs from canonical lignin-active oxidoreductases like laccases and peroxidases. This discovery presents new opportunities for the oxyfunctionalization and valorization of lignin-derived compounds. Notably, some short PPOs funnel guaiacyl- and syringyl-type substrates into the same products, offering a potential new strategy to make lignin depolymerization products more uniform and enhance their value for chemical and material applications. Building on their activity with monomeric lignin model compounds, further studies are needed to explore the activity of short PPOs on more complex lignin model oligomers, ultimately leading to real lignin polymers. A recent study reported β-ether bond cleavage in the lignin-like model dimer guaiacylglycerol-β-4-methylumbelliferone (GB-MU) and tricin release from wheat straw by a short PPO but did not investigate the cleavage mechanisms [2]. Here, we examine in detail the activity of new fungal short PPOs on a set of phenolic β-O-4 linked lignin model dimers, including variations in guaiacyl and syringyl units, where we address factors such as pH and the challenge of minimizing polymerization.