TYR and freckles: Besides, UV-produced free radicals could directly excite PI3K/Akt signaling pathway to activate NF-κB signal, which would promote the transcription of iNOS in keratinocyte to produce NO, further enhancing tyrosinase activity in melanocytes and ultimately increasing melanin formation [55, 127]; more importantly, it was discovered that OS indicators (like MDA, NO, ROS) positively correlated with melasma area severity index (MASI) in chloasma [55], further confirming the catalytic role of OS in chloasma pathogenesis.