The extensive diffusion of plastic materials over the last decades has become a critical environmental challenge, threatening ecosystems worldwide. From the accumulation of plastic debris in soils to the pervasive spread of micro-and nanoplastics in marine environments, the adverse effects of plastic pollution are well-documented. Among these polymers, polyethylene terephthalate (PET) stands out due to its widespread use, driven by its distinctive properties. Durability, gas and water barrier properties, transparency, and low cost makes this material ideal for manufacturing single-use food and beverage containers. However, the fate of these manufacts after their use is still far from being environmentally sustainable. Moreover, the synthesis of these polymers is sourced by fossil raw materials, whose availability is limited and the value chain is highly energy demanding. Finally, PET recycling is still not an attractive solution because processed materials lose most their properties and the treatment is economically disadvantageous compared to the production from fossil fuel monomers. To address these challenges, bio-based packaging materials have emerged as a promising alternative to reduce the carbon footprint and to lower environmental impact than petroleum-based plastics. A remarkable example is the sugar-derived polyethylene-2,5-furan dicarboxylate (PEF), which combines reduced greenhouse gas emissions during synthesis with non-toxicity and comparable mechanical properties to PET, positioning it as a valuable potential substitute in the near future. In this scenario, finding efficient solutions for the sustainable and efficient upcycling of plastic debris is mandatory. In the last years, an environmentally friendly and sustainable alternative to conventional methods has been offered by enzymatic degradation. Several bacterial enzymes were discovered able to cleave the polymeric plastic chains, including cutinases, lipases, and esterases, and grouped in the family of "PET-hydrolyzing enzymes" (PHEs). A breakthrough in this field occurred in 2016 with the discovery of a bacterium, named Ideonella Sakaiensis 201-F6 that used PET as a major nutrient thanks to the secretion of two hydrolases: PETase and MHETase. Working synergistically, PETase cleaves the PET chains mainly into mono(hydroxyethyl terephthalate) (MHET), bis(hydroxyethyl terephthalate) (BHET), terephthalic acid (TPA), and ethylene glycol (EG; Figure ), whereas MHETase completes the process, converting MHET and BHET into their minimal chemical moieties. Remarkably, PETase has also demonstrated significant hydrolytic activity against PEF, depolymerizing this semi-aromatic polyester into mono(2-hydroxyethyl furanoate) (MHEF), bis(2-hydroxyethyl furanoate) (BHEF) and 2-5 furandicarboxylic acid (FDCA) and ethylene glycol (EG; Figure ). From a structural point of view, PETase resembles the folding of an 𝛼/𝛽 hydrolase, characterized by a central nine-stranded twisted 𝛽-strand, surrounded by seven 𝛼-helices. The catalysis is exerted by a catalytic triad composed of serine, histidine, and aspartate residues (S160, H237, and D206) in the active site, which encompasses also the residues tryptophane, tyrosine, methionine and isoleucine (W185, Y87, M161, and I208) to support the substrate recognition and binding (Figure ). The key peculiarity of PETase is that it achieves peak activity at relatively low temperature (≈ 30°C) thanks to the flexibility of the binding pocket, which facilitates the accommodation of the polymeric chains. In contrast, its catalytic efficiency drops at a higher temperature because of its poor thermostability. While these characteristics facilitate new pathways for managing plastic waste under moderate conditions, they may also limit these systems' applicability for degrading high-crystallinity PET waste, which requires operating near the material's glass transition temperature (≈ 79 °C). For this reason, the recent years have witnessed the introduction of a number of variants of PETase, which were strategically modified to improve its structural stability and catalytic activity. ). The protein is colored according to its secondary structure elements: yellow for the nine 𝛽-strands, orange for the seven 𝛼-helices, red for the three 310-helices and grey for unfolded regions. Distinctive amino acids are also shown in sticks: cysteines C273 -C289 and C203 -C239 forming two disulfide bridges are colored in cyan, the residues S160, H237, D206 (catalytic triad), W185, I208, M161 and Y87 forming the active site are colored in pink. Close-up views of the catalytic site with the (D) PET4 and (E) PEF4 bound chains, represented as ice blue and green sticks, respectively, are shown.